Methods, devices, and systems for postconditioning with clot removal

ABSTRACT

New devices, systems, and methods are disclosed for preventing, treating, and/or at least minimizing ischemia and/or reperfusion injury by restoring and/or modulating blood flow, particularly in the cerebral vasculature where blood vessels are narrow and tortuous. These devices, systems, and methods make it possible for a clinician to adequately and systematically restore blood flow to ischemic tissue while simultaneously modulating the blood flow to minimize reperfusion injury.

RELATED APPLICATIONS

This application claims priority to and incorporates by reference the entire contents of U.S. Provisional Application No. 61/668,408, filed on Jul. 5, 2012 and U.S. patent application Ser. No. 13/844,728 filed on Mar. 15, 2013.

TECHNICAL FIELD

The present disclosure relates generally to methods, devices, and systems for treating vascular disorders. More specifically, the present disclosure relates to methods, devices, and systems for restoring blood flow by, e.g., removing blood clots, and/or modulating post-reperfusion blood flow.

BACKGROUND OF THE INVENTION

Ischemia, the restriction of blood supply to tissue, may result in tissue damage in a process known as ischemic cascade. Damage includes, but is not limited to, shortage of metabolic requirements (i.e., oxygen and glucose), build-up of metabolic waste products, inability to maintain cell membranes, mitochondrial damage, and eventual leakage of autolysing proteolytic enzymes into the cell and surrounding tissues. Brain ischemia may be chronic, e.g., leading to vascular dementia, or acute, e.g., causing a stroke. A stroke is the rapid decline of brain function due to a disturbance in the supply of blood to the brain caused by a clot or hemorrhage in a blood vessel. A clot may contain a thrombus, embolus, and/or thromboembolus. An ischemic stroke is a stroke in which a blood vessel is restricted or occluded by a clot.

Ischemic stroke is the fourth leading cause of death in the United States, affecting over 795,000 patients per year and costing tens of billions of healthcare dollars. See, e.g., Veronique L. Roger et al., “Heart Disease and Stroke Statistics—2012 Update: A Report from the American Heart Association.” 125 Circulation e2-e220 (2012). Furthermore, patients who survive an ischemic stroke often require rehabilitation and management of symptoms including loss of brain function, motor skills, and memory. The extent of infarction (i.e., destruction of brain tissue) correlates with the extent of these lingering effects of the stroke and the mortality rate.

Of the existing treatment options for ischemic stroke, an older method, but still the primary method used in the United States, is to treat the clot with a clot-dissolving enzyme known as tissue plasminogen activator (“tPA”). The use of tPA has two primary drawbacks. First, tPA has limited effectiveness, in both dissolving clots and providing overall benefits for the patients. Many patients do not qualify for tPA treatment because they do not arrive at the hospital within the effective time window of approximately 4.5 hours after the onset of stroke. Even when used within that window, tPA achieves only a limited decrease in the overall mortality rate. Second, tPA may present adverse effects, such as serious internal bleeding. See, e.g., Götz Thomalla et al., “Two Tales: Hemorrhagic Transformation But Not Parenchymal Hemorrhage After Thrombolysis Is Related to Severity and Duration of Ischemia: MRI Study of Acute Stroke Patients Treated with Intravenous Tissue Plasminogen Activator Within 6 Hours,” 38(2) Stroke 313-18 (2007).

A newer method to treat ischemic stroke is mechanical thrombectomy, in which a device physically engages with a clot and is used to drag the clot out of the body. Usually, an operator. e.g., a surgeon, first establishes a path for the thrombectomy device to reach a clot in the cerebral vasculature by inserting an initial guidewire (or guiding catheter) into an artery in a lower region of the body, such as the femoral artery. Then, the operator steers the guidewire through the arteries leading up to the brain and just past (i.e., distal to) the position of the clot. Favoring whichever path poses least resistance, the guidewire passes either between the clot and the blood vessel wall or through the clot. The operator inserts a microcatheter over the initial guidewire to follow its path until reaching a position distal to the clot. The initial guidewire may be removed and replaced with a new guidewire (hereinafter “pushwire” to differentiate from an initial guidewire). This pushwire has a thrombectomy device attached to its distal end to engage with the clot.

Currently, the most successful class of thrombectomy devices is based on neurovascular stent technology. Like stents, which are self-expandable and generally cylindrical, these devices tend to expand to the shape of the blood vessel walls. Thrombectomy devices may comprise thin metal struts arranged to create a cell pattern. During device expansion, a clot may become enmeshed in the cells and compressed against a blood vessel wall. At this point, blood flow may be partially or fully restored in the vessel, thus relieving ischemia.

Unfortunately, abrupt restoration of blood supply to ischemic tissues may cause reperfusion injury, which is additional damage to cerebral tissue, above and beyond damage caused by the ischemia itself. For example, reperfusion results in a sudden increase in tissue oxygenation, causing a greater production of free radicals and reactive oxygen species that damage cells. The restored blood flow also brings more calcium ions to the tissues causing calcium overloading that may result in potentially fatal cardiac arrhythmias and accelerated cellular self-destruction. Furthermore, reperfusion may exaggerate the inflammation response of damaged tissue, triggering white blood cells to destroy otherwise viable damaged cells.

Reperfusion injury is highly significant and can visibly increase the infarct size (i.e., destroyed tissue) by as much as 30%. See. e.g., Andrew Tsang et al., “Myocardial Postconditioning: Reperfusion Injury Revisited,” 289(1) Am. J. Physiol. Heart & Circ. Physiol. H2-7 (2005); Heng Zhao et al., “Interrupting Reperfusion as a Stroke Therapy: Ischemic Postconditioning Reduces Infarct Size After Focal Ischemia in Rats,” 26(9) J. Cereb. Blood Flow & Metab. 1114-21 (2006); Giuseppe Pignataro et al., “In Vivo and In Vitro Characterization of a Novel Neuroprotective Strategy for Stroke: Ischemic Postconditioning,” 28(2) J Cereb. Blood Flow & Metab. 232-41 (2008).

Existing thrombectomy devices and/or systems do not systematically or even adequately control the restoration of blood flow so as to minimize and/or prevent reperfusion injury. Thus far, the prevention of reperfusion injury has been limited to the field of interventional cardiology. During the management of an ischemic event in the heart, a cardiologist will treat the occlusion of a vessel with stents and/or balloon angioplasty to restore blood flow. Following reperfusion, a cardiologist may use an inflatable balloon to block and unblock blood flow through the vessel in intervals, thus modulating the resumed blood flow and minimizing reperfusion injury in a process called postconditioning.

Existing postconditioning devices and/or systems (e.g., catheters with high longitudinal rigidity and large diameters) are designed for the large arteries of the heart; however, the narrow and tortuous arteries of the cerebral vasculature render these existing devices and/or systems inadequate or at least less desirable in the context of ischemic stroke.

Existing postconditioning devices and/or systems also fail to incorporate simultaneous clot capture. In order to initiate reperfusion and perform postconditioning simultaneously, both a reperfusion member and flow modulation member must be disposed concurrently in the same region. Particularly in the brain, where space constraints make it difficult to fit both a reperfusion member and a flow modulation member, no existing postconditioning devices and/or systems are designed to simultaneously deploy a reperfusion member, such as a clot-capturing reperfusion member, and perform postconditioning for the ischemic tissue.

Thus, there remains a need for postconditioning devices, systems, and methods designed to prevent, minimize, and/or treat ischemic stroke and/or reperfusion injury by restoring and modulating blood flow in the cerebral vasculature.

Meanwhile, in addition to overlooking reperfusion injury, existing thrombectomy devices and/or systems are not designed to consistently bind with, capture, and/or retrieve clots. In fact, only about 30% of clots are successfully retrieved on a first pass (i.e., a deployment of the thrombectomy device). After five passes, 10% of clots still remain lodged. Furthermore, in 10% of cases, reperfusion is not even achieved while a thrombectomy device and/or system is engaged with the clot. Thus, there also remains a need for thrombectomy devices and/or systems that not only increase binding with clots but also increase reperfusion by creating a greater gap within the clot or between the clot and the blood vessel wall.

SUMMARY OF THE INVENTION

The devices, systems, and methods of the present invention are based on the recognition of the anatomic and physiologic principles, particularly in the cerebral vasculature, underlying reperfusion injury and ischemic stroke. The prior thrombectomy and/or postconditioning art fail to recognize the importance of, and provide methods and systems for, adequately controlling the restoration of blood flow so as to minimize and/or prevent reperfusion injury. The prior art also fails to sufficiently address the arterial space constraints in the brain that limit the positioning of devices and/or systems.

As described more fully in this specification, embodiments of the present invention include methods for preventing, treating, and/or at least minimizing ischemic stroke and/or reperfusion injury by restoring and/or modulating blood flow, particularly in the cerebral vasculature. The methods, generally referred to as postconditioning, are performed with devices and systems, which are adapted for use in the performance of the controlled restoration and/or modulating blood flow. The devices, systems, and methods described herein make it possible for a clinician to adequately and systematically restore blood flow to ischemic tissue while simultaneously modulating the blood flow to minimize reperfusion injury. Some embodiments of the present invention specifically enable postconditioning in the challenging dimensional constraints of the brain. Some embodiments further enable improved binding with clots and reperfusion by creating an increase within the cross-sectional area between the clot and the blood vessel wall or in the clot itself, particularly for clots that are resistant to the weak engagement of existing thrombectomy devices and/or systems.

The present invention addresses an unmet clinical need to control reperfusion and prevent ischemia. Embodiments of the present invention include systems and methods for preventing, treating, and/or at least minimizing ischemic stroke and/or reperfusion injury by restoring and/or modulating blood flow, particularly in the cerebral vasculature. The systems and methods of the present invention make it possible for a clinician to systematically restore blood flow to ischemic tissue while simultaneously modulating the blood flow to minimize reperfusion injury. Some embodiments of the present invention specifically enable postconditioning in the challenging dimensional constraints of the brain (i.e. narrow and tortuous arteries of the cerebral vasculature).

Some embodiments further enable improved binding with clots and reperfusion by creating an increase in cross-sectional area between the clot and the blood vessel wall or within the clot itself, particularly for clots that are resistant to the weak engagement of existing thrombectomy devices and/or systems. The embodiments of the present invention include two features, a reperfusion member and a flow modulation member. In an embodiment, the flow modulation member may be coupled to a proximal region of the catheter and include an inflatable balloon able to reversibly decrease and increase the flow of fluid through the blood vessel at least twice, and so modulate blood flow through the blood vessel. According to other embodiments, the flow modulation member can take an umbrella-like shape. In other embodiments various pharmacological agents can be delivered to the treatment site to reduce the size or effect of the ischemia.

These embodiments of the present invention are primarily directed, therefore, to initiating reperfusion and performing postconditioning simultaneously in a blood vessel with improved devices, systems, and methods. These embodiments are designed to prevent, minimize, and/or treat ischemia and/or reperfusion injury by restoring and modulating blood flow in the cerebral vasculature, as well as vasculature in the lungs, heart, pelvis, legs, and any other part of a cardiovascular system in a living being (or in vitro models thereof).

The embodiments of the invention include, described in proximal to distal order, an expandable flow modulation device located at the exterior of the catheter, a seal located at the interior of the catheter, and a stent attached to a wire that can protrude from the distal portion of the catheter. The expandable membrane can manifest itself in a variety of formats, including, but not limited to, an expandable membrane (“balloon”) and a collapsible diaphragm (“umbrella”). The seal format includes, but is not limited to, spherical, conical, ovoid, and cylindrical, with optional tapering at one or both ends of the device. The stent used to capture the clot has formats including, but not limited to, a mesh spherical surface, a mesh ovoid surface, and a mesh cylindrical surface, which opens upon protrusion from the catheter. The stent remains in place during the clot-capture process, as the catheter depth is adjusted to simultaneously regulate reperfusion with the aforementioned expandable flow modulation device at the exterior of the catheter. Expansion and contraction of the exterior can be conducted by methods including, but not limited to, translation of components to effect expansion, pneumatics which can drive gas to expand the flow modulation device, hydraulics which can drive liquid to expand the flow modulation device, and electromagnetic mechanisms.

In one embodiment, a method includes introducing a device into a cerebral blood vessel that is at least partially blocked by a clot, applying pressure to an internal wall of the cerebral blood vessel to enhance blood flow in the vessel, postconditioning to reduce reperfusion injury, removing at least part of the clot from the vessel, removing the device from the cerebral blood vessel, the application of pressure, the removal of the clot, and the postconditioning occurring after the device is introduced and before the device is removed from the vessel.

In an embodiment, the method step of postconditioning includes at least partially occluding the vessel. In an embodiment, the method steps of applying, removing, and postconditioning comprise a single medical procedure. In an embodiment, the method step of postconditioning further includes selectively permitting flow through the vessel and reducing flow through the vessel in prescribed sequence.

In one embodiment, an apparatus includes a catheter, an expandable membrane (“balloon”) disposed on the catheter at a distal end of the catheter, the catheter including an orifice for inflating the balloon, a stent in the vicinity of a distal end of a wire that extends through a lumen to an end of the catheter, and a sealing interface between the wire and the lumen, nearer to the distal end of the catheter than is the orifice for inflating the balloon, that is adapted to seal the lumen so that the balloon may be inflated.

In an embodiment, the sealing interface of the apparatus includes an outwardly facing surface on the wire and an inwardly facing surface on the lumen. In an embodiment, the inwardly facing sealing surface of the lumen has a smaller diameter than the other portions of the lumen of the catheter. In an embodiment, the outwardly facing surface of the wire has a larger diameter than other portions of the wire.

In one embodiment, a device capable of transporting fluid and a pushwire bearing a flow restoration member includes a catheter with a lumen that has an inner surface, a pushwire, including a sealing ring disposed toward the distal end of the pushwire, wherein the sealing ring is sized to sealingly engage the inner surface of the catheter so that when engaged the sealing ring substantially blocks flow of the fluid through the catheter so that inflating fluid may be directed into the balloon so as to cause inflation of the balloon.

In an embodiment, the device is capable of transporting fluid that contains one or more of the following: contrast agent, tPA, cyclosporine, calpain inhibitors, sodium-calcium Na+/Ca2+ exchange inhibitors, monoclonal antibodies, temperature reducing agents, agents that slow cell metabolism, plasminogen activator, agents that may aid in removing a clot agents that aid in dissolving, dislodging, or macerating clots, pharmaceuticals or compounds commonly used for treating clots, preventing restenosis, agents that prevent/reduce or accelerate healing of reperfusion injury, intravascular device coatings such as vasodilators, nimodipine, sirolimus, paclitaxel, anti-platelet compounds and agents that promote the entanglement or attachment of a clot with a reperfusion member such as fibronectin.

In one embodiment, an assembly configured to treat ischemia in a patient includes a catheter with a proximal region, a distal region, and a single lumen, a flow modulation member coupled to the proximal region of the catheter and including an inflatable balloon able to reversibly decrease and increase the flow of fluid through the blood vessel at least twice, and thereby modulate blood flow through the blood vessel, wherein the inflatable balloon has a balloon inflation aperture continuous with the single lumen and able to receive inflating fluid from the single lumen, a pushwire with a proximal end and a distal end, wherein the pushwire is at least partially within the single lumen, a flow restoration member for increasing the flow of blood through the clot, coupled to the distal end of the pushwire, and one or more sealing members adapted to decrease the flow rate of inflating fluid leaving the single lumen.

In an embodiment, one of the one or more sealing members of the assembly is made of an electroactive compound, whereby applying and/or altering an electric current applied to the pushwire causes the electroactive sealing member to expand so as to provide more resistance to the flow of fluid through the catheter, wherein the flow modulation member is capable of expanding to produce a desired seal. In an embodiment, the assembly further is adapted to operate with a pressure of the fluid less than 5 atm. In an embodiment, the flow restoration member for increasing the flow of blood through a blood vessel beyond a clot includes a self-expanding scaffold, adapted to engage a clot in a blood vessel.

In one embodiment, an aspect of the invention is a method comprising the steps of introducing a device into a cerebral blood vessel that is at least partially blocked by a clot and applying pressure to an internal wall of the cerebral blood vessel to enhance blood flow in the vessel. Postconditioning is then applied to reduce reperfusion injury. Then, in one embodiment, the method involves removing at least part of the clot from the vessel and then removing the device from the cerebral blood vessel. Each of the steps in this embodiment, the application of pressure, the removal of the clot, and the postconditioning occurs after the device is introduced and before the device is removed from the vessel. In this method, the step of postconditioning may comprise at least partially occluding the vessel. Another aspect of this method includes performing the steps of applying, removing, and postconditioning comprise a single medical procedure. In another aspect of the method the step of postconditioning may include selectively permitting flow through the vessel and reducing flow through the vessel in prescribed sequence.

Another aspect of the invention is an apparatus that includes a catheter, a balloon disposed on the catheter at a distal end of the catheter. The catheter according to the embodiment includes an orifice for inflating the balloon. A stent is provided in the vicinity of a distal end of a wire that extends through a lumen to an end of the catheter. In another aspect of this embodiment, a sealing interface is disposed between the wire and the lumen, nearer to the distal end of the catheter than is the orifice for inflating the balloon that is adapted to seal the lumen so that the balloon may be inflated. The sealing interface in this embodiment may include an outwardly facing surface on the wire and an inwardly facing surface on the lumen. Additionally, the inwardly facing sealing surface of the lumen has a smaller diameter than the other portions of the lumen of the catheter. In another aspect of this embodiment, the outwardly facing surface of the wire has a larger diameter than other portions of the wire.

A further embodiment of the invention includes a device capable of transporting fluid and a pushwire bearing a flow restoration member. In this embodiment, the device includes a catheter, which includes a lumen that has an inner surface, a pushwire that includes a sealing ring disposed toward the distal end of the pushwire. The sealing ring is sized to sealingly engage the inner surface of the catheter so that when engaged the sealing ring substantially blocks flow of the fluid through the catheter.

In another embodiment, an assembly configured to treat ischemia in a patient includes a catheter with a proximal region, a distal region, and a single lumen and a flow modulation member coupled to the proximal region of the catheter and including an inflatable balloon able to reversibly decrease and increase the flow of fluid through the blood vessel at least twice, and so modulate blood flow through the blood vessel. The inflatable balloon according to another embodiment has a balloon inflation aperture continuous with the single lumen and able to receive inflating fluid from the single lumen, a pushwire with a proximal end and a distal end, wherein the pushwire is at least partially within the single lumen, a member for increasing the flow of blood through the clot, coupled to the distal end of the pushwire; and one or more sealing members adapted to decrease the flow rate of inflating fluid leaving the single lumen.

The catheter in the above embodiment may comprise various devices, which can be used to seal the catheter, which can, when desired, inflate a balloon for a reperfusion. A first section in the proximal region and a second section in the distal region, the area in the second section of the lumen, in the plane normal to the central axis of the catheter, being smaller than the area in the first section of the lumen, in the plane normal to the central axis of the catheter. A sealing member may comprise a protrusion with an outwardly facing surface attached to the pushwire at a location on the pushwire proximal to the flow restoration member. The protrusion slows the flow of fluid through the lumen when the protrusion engages an inwardly facing surface at the distal region of the catheter.

In another embodiment, a sealing member may comprise a sealing tip at the distal end of the catheter. A luminal edge of the sealing tip is designed to come in close proximity with a sealing surface of the pushwire and slows the flow of fluid through the lumen when the sealing surface pushwire is placed through the sealing tip. In this embodiment, the sealing tip allows the flow restoration member to pass the sealing tip when the catheter is translated relative to the pushwire.

Another aspect of the inventive method disclosed in this application includes a method of using an assembly able to treat ischemia in a patient, the steps of the method include first, identifying a blood clot in a blood vessel: second, inserting a catheter into the blood vessel, the catheter including a proximal region, a distal region, and a single lumen, wherein a pushwire with a proximal end and a distal end is placed at least partially within the single lumen; third, modulating blood flow in the blood vessel by selectively decreasing and increasing the flow of fluid through the blood vessel with a flow modulation member at least twice. The flow modulation member is coupled to the distal region of the catheter and includes an inflatable balloon having a balloon inflation aperture with the single lumen and adapted to receive inflating fluid from the single lumen, wherein one or more sealing members are provided along the lumen to reduce the volumetric flow rate of inflating fluid leaving the single lumen; and fourth, increasing the flow rate in the blood vessel by translating the catheter relative to the pushwire to deploy a flow restoration member, wherein the flow restoration member is coupled to the pushwire near the distal end of the pushwire and comprises a self-expanding scaffold able to engage the clot.

An aspect of this method includes the feature that the catheter used in the method comprises a first section in the proximal region and a second section in the distal region, the area in the second section of the lumen, in the plane normal to the central axis of the catheter, being smaller than the area in the first section of the lumen, in the plane normal to the central axis of the catheter. Additionally, another aspect of the invention includes the feature that one or more a sealing ring may be coupled to the pushwire at a location in the single lumen proximal to the flow restoration member, wherein the sealing ring is able to engage the distal region of the catheter. Additionally and alternatively, the one or more a sealing tip may be coupled to the distal end of the catheter, and the sealing tip is adapted to selectively sealingly engage when the catheter is translated relative to the pushwire. In addition, according to this embodiment, the sealing tip is able to allow the flow restoration member to pass the sealing tip when the catheter is translated relative to the pushwire.

Another embodiment of the invention includes an assembly able to treat ischemia in a patient with an intermediate catheter with a proximal region, a distal region, and a single intermediate lumen. A flow modulation member is coupled to the distal region of the intermediate catheter and comprises an inflatable balloon to reversibly decrease and increase the flow of fluid through a blood vessel for modulating blood flow through the blood vessel. The inflatable balloon has a balloon lumen continuous with the single intermediate lumen and receives inflating fluid from the lumen of the intermediate catheter. Also included in this assembly is a microcatheter with a single microcatheter lumen and the microcatheter is at least partially within the lumen of the intermediate catheter. A pushwire having a proximal end and a distal end is adapted to be at least partially within the lumen of the microcatheter. Also included in the assembly of this embodiment is a flow restoration member coupled to the distal end of the pushwire and comprising a self-expanding scaffold able to engage a clot in a blood vessel and one or more sealing members able to reduce the volumetric flow rate of inflating fluid leaving the single intermediate lumen.

In some embodiments of this invention, the self-expanding scaffold is a stent. Further, in some embodiments, the intermediate catheter includes a first section in the proximal region and a second section in the distal region, the area in the second section of the lumen, in the plane normal to the central axis of the catheter, being smaller than the area in the first section of the lumen, in the plane normal to the central axis of the intermediate catheter. One or more sealing members may be included that have a protrusion which reduces the space between the pushwire and the protrusion through which fluid can flow around the location of the protrusion coupled to the microcatheter, so that the protrusion may facilitate the inflation of the balloon when the protrusion is within or near the distal region of the intermediate catheter. In some embodiments the protrusion is annular. Additionally or alternatively, a sealing tip may be coupled to the distal end of the intermediate catheter, wherein a luminal edge of the sealing tip comes in close proximity with the pushwire and slows the flow of fluid through the lumen when the pushwire is placed through the sealing tip.

Another aspect of the method of this invention may include a method of using an assembly able to treat ischemia in a patient. The steps of this method may include, identifying a target blood clot in a blood vessel; inserting into the blood vessel an intermediate catheter with a proximal region, a distal region, and a single intermediate catheter lumen, wherein a microcatheter with a single microcatheter lumen is at least partially within the single intermediate catheter lumen, wherein a pushwire with a proximal end and a distal end is at least partially within the lumen of the microcatheter; modulating blood flow in the blood vessel by reversibly decreasing and increasing the flow of fluid through the blood vessel with a flow modulation member at least twice, wherein the flow modulation member is coupled to the distal region of the intermediate catheter and comprises an inflatable balloon having a balloon lumen continuous with the single intermediate lumen and able to receive inflating fluid from the single intermediate lumen; reducing the rate of inflating fluid leaving the single intermediate lumen by translating the intermediate catheter relative to the microcatheter so that the protrusion slows the flow of fluid through the lumen when the protrusion engages the distal region of the intermediate catheter; and increasing the flow rate in the blood vessel by translating the catheter relative to the pushwire to deploy a flow restoration member.

In another aspect of the invention the flow restoration member used in the method may be coupled to the pushwire near the distal end of the pushwire and includes a structure or material for addressing a clot, such as macerating, transforming or dissolving the clot. The structure or material will engage the clot by either direct physical contact, direct/indirect energy contact or by distribution of pharmacological agent. In one embodiment the structure could be a scaffold, which may be self-expanding and capable of addressing the clot by direct physical contact. In still another aspect of the invention, the catheter used in the method may include a first section in the proximal region and a second section in the distal region, the area in the second section of the lumen, in the plane normal to the central axis of the catheter, being smaller than the area in the first section of the lumen, in the plane normal to the central axis of the catheter. The method may employ one or more sealing members used in the method comprise a protrusion coupled to the pushwire at a location in the single lumen proximal to the flow restoration member. The protrusion slows the flow of fluid through the lumen when the protrusion engages the distal region of the catheter. Additionally or alternatively a sealing tip may be coupled to the distal end of the catheter, wherein the sealing tip is able to engage the pushwire when the catheter is translated relative to the pushwire. Additionally, the luminal edge of the sealing tip comes in close proximity with the pushwire and slows the flow of fluid through the lumen when the pushwire is placed through the sealing tip.

In still another embodiment of the invention an assembly able to treat ischemia in a patient is described. In this embodiment, the invention includes a catheter with a proximal end, a distal end, and at least two catheter lumina; one or more flow modulation members coupled to the catheter and comprising an inflatable balloon able to reversibly decrease and increase the flow of fluid through the blood vessel with a flow modulation member at least twice, wherein the inflatable balloon has a balloon lumen continuous with a first catheter lumen and able to receive inflating fluid from the first catheter lumen, wherein the distal end of the first catheter lumen is closed; one or more pushwires with a proximal end and a distal end, wherein the pushwire is placed at least partially within a second catheter lumen; and one or more flow restoration members coupled to the pushwire near the distal end of the pushwire. In this embodiment, a flow restoration member may include a self-expanding scaffold able to engage a clot in a blood vessel.

In another method of the invention, the assembly is able to treat ischemia in a patient. In this embodiment the use of the assembly includes the following steps: identifying a blood clot in a blood vessel; inserting a catheter into the blood vessel the catheter including a proximal end, a distal end, and at least two catheter lumina, wherein a pushwire with a proximal end and a distal end is placed at least partially within a first catheter lumen; modulating blood flow in the blood vessel by reversibly decreasing and increasing the flow of fluid through the blood vessel with a flow modulation member at least twice, wherein the flow modulation member is coupled to the proximal region of the catheter and comprises an inflatable balloon having a balloon lumen continuous with a second catheter lumen receiving inflating fluid from the second catheter lumen, wherein one or more sealing members slow the flow rate of the inflating fluid that leaves the second catheter lumen; and increasing the flow rate in the blood vessel by translating the catheter relative to the pushwire to deploy a flow restoration member. In this method, the flow restoration member is coupled to the pushwire near the distal end of the pushwire and comprises a self-expanding scaffold able to engage the clot.

In still a further embodiment of the invention an assembly able to treat ischemia in a patient includes: an intermediate catheter with a proximal end, a distal end, and at least two intermediate catheter lumina; one or more flow modulation members coupled to the intermediate catheter and comprising an inflatable balloon or membrane able to reversibly reduce and increase the flow of fluid through the blood vessel at least twice for modulating blood flow through the blood vessel, wherein the inflatable balloon has a connecting lumen continuous with a first intermediate catheter lumen and receives inflating fluid from the first intermediate catheter lumen, wherein the distal end of the first intermediate catheter lumen is closed; one or more microcatheters with a microcatheter lumen, wherein the microcatheter is at least partially within a second intermediate catheter lumen; one or more pushwires with a proximal end and a distal end, wherein the pushwire is at least partially within the microcatheter lumen; and one or more flow restoration members coupled to near the distal end of the pushwire and comprising a self-expanding scaffold that engages a clot in a blood vessel.

In another embodiment of the method according to the invention an assembly is used to treat ischemia in a patient. The steps of the method include: identifying a blood clot in a blood vessel; inserting into the blood vessel an intermediate catheter with a proximal end, a distal end, and at least two intermediate catheter lumina, wherein a microcatheter with a microcatheter lumen is placed at least partially in a first intermediate catheter lumen, wherein a pushwire with a proximal end and a distal end is placed at least partially in the microcatheter lumen; modulating blood flow in the blood vessel by reversibly decreasing and increasing the flow of fluid through the blood vessel with a flow modulation member at least twice, wherein the flow modulation member is coupled to the distal region of the intermediate catheter and comprises an inflatable balloon having a balloon lumen continuous with a second intermediate catheter lumen and able to receive inflating fluid from the second intermediate catheter lumen: and increasing the flow of blood in the blood vessel by translating the catheter relative to the pushwire to deploy a flow restoration member, wherein the flow restoration member is coupled to pushwire near the distal end of the pushwire and comprises a self-expanding scaffold able to engage the clot.

The present invention in one embodiment is an assembly adapted to engage a clot in a blood vessel. The assembly includes a catheter with a proximal end, a distal end, and at least one lumen; a pushwire with a proximal end and a distal end, wherein the pushwire is at least partially within the at least one lumen; and a reperfusion member coupled to the pushwire near the distal end of the pushwire and comprising a self-expanding scaffold that is capable of engaging a clot in a blood vessel when the catheter is moved so that the expanding scaffold is not completely within the catheter. The scaffold includes open cells formed by a pattern of struts and the cells have a hexagonal cell shape able to facilitate engagement with the clot.

The present invention in another embodiment is an assembly adapted for engaging a clot in a blood vessel. The assembly includes a catheter with a proximal end, a distal end, and at least one lumen; one or more pushwires with a proximal end and a distal end, wherein the pushwire is at least partially within the at least one lumen; and a reperfusion member coupled to the distal end of the pushwire and comprising a self-expanding scaffold to engage a clot in a blood vessel when the catheter is retracted so as to at least partially not surround the expanding scaffold, wherein the scaffold comprises open cells formed by a pattern of struts, wherein at least one of the struts has a cross-sectional shape with an angle less than 180 degrees oriented such that the angle protrudes outward from the scaffold to facilitate engagement with the clot.

According to another method of the present invention a clot in a blood vessel can be engaged. The method includes the steps of: identifying a blood clot in a blood vessel; inserting into the blood vessel a catheter with at least one lumen, wherein a pushwire with a proximal end and a distal end is placed at least partially within the at least one lumen, wherein a reperfusion member comprising a self-expanding scaffold is coupled to the distal end of the pushwire; aligning the distal end of the catheter within or distal to the clot; retracting the catheter to unsheathe and allow the scaffold to expand within the blood vessel, wherein the scaffold comprises open cells formed by a pattern of struts, wherein the cells have a hexagonal cell shape able to facilitate engagement with the clot; and extracting any clot material engaged by the scaffold by removing the catheter and the pushwire from the blood vessel.

In still another embodiment of the invention, the specification describes a method for engaging a clot in a blood vessel. The steps include: identifying a blood clot in a blood vessel; inserting into the blood vessel a catheter with at least one lumen, wherein a pushwire with a proximal end and a distal end is placed at least partially within the at least one lumen, wherein a reperfusion member comprising a self-expanding scaffold is coupled to the pushwire near the distal end of the pushwire; placing the distal end of the catheter close to the distal end of the clot; retracting the catheter to unsheathe and allow the scaffold to expand within the blood vessel, wherein the scaffold comprises open cells formed by a pattern of struts, wherein at least one of the struts has a cross-sectional shape with an angle less than 180 degrees oriented such that the angle protrudes outward from the scaffold to facilitate engagement with the clot; and extracting any clot material engaged by the scaffold by removing the catheter and the pushwire from the blood vessel.

In another aspect of the invention assembly is disclosed that is able to prevent and/or treat ischemic stroke in a patient. The assembly according to this embodiment includes a flow restoration member comprising a self-expanding scaffold capable of engaging a clot in a cerebral blood vessel; and a flow modulation member to reversibly decreasing and increasing the flow of fluid through the blood vessel with the flow modulation member at least twice, performing one or more postconditioning cycles in the cerebral blood vessel, wherein the members are able to be used simultaneously to prevent and/or treat ischemic stroke.

The invention in another embodiment includes a method of preventing and/or treating ischemic stroke in a patient. In this embodiment the steps of the method include: identifying a blood clot in a cerebral blood vessel; inserting an assembly able to prevent, mitigate and/or treat ischemic stroke into the blood vessel, the assembly comprising: a flow restoration member comprising a self-expanding scaffold able to engage a clot in a cerebral blood vessel; and a flow modulation member able to modulate blood flow in a cerebral blood vessel, wherein the members are able to be used simultaneously to prevent, mitigate, reduce and/or treat ischemic stroke: deploying the scaffold to restore blood flow in the cerebral blood vessel; and performing one or more postconditioning cycles with the flow modulation member by reversibly decreasing and increasing the flow of fluid through the blood vessel at least twice.

The present invention is according to another embodiment, a device for modulating blood flow, the device includes: a flow modulation member having a plurality of self-expanding struts and a membrane capable of blocking blood flow; a pushwire, wherein the flow modulation member is attached to the pushwire; and a microcatheter with a lumen sized to receive at least a portion of the pushwire, the membrane capable of blocking blood flow attached to the microcatheter, wherein relative movement between the pushwire and the microcatheter in one direction unsheathes the flow modulation member, allowing the flow modulation member to expand, and wherein relative movement between the pushwire and the microcatheter in the opposite direction re-sheathes the flow modulation member, causing the flow modulation member to retract.

Another embodiment of the present invention is a device for modulating blood flow, the device includes: a flow modulation member comprising a microcatheter and an inflatable balloon attached to the microcatheter adapted to selectively reduce blood flow; a fluid conduit associated with the microcatheter for conducting inflation fluid between a proximal side of the microcatheter and the balloon, wherein the conduit is flexible and contiguous with the microcatheter. In this embodiment, the conduit may be a tube that travels outside the microcatheter. The conduit according to this embodiment may be disposed in a helical arrangement outside the microcatheter. The conduit of this embodiment may be a hollow space between an inner wall and an outer wall of the microcatheter, the inner and outer wall of the microcatheter connected at selected locations along its length.

In another aspect of the invention, device for engaging with a blood clot or embolus includes: a reperfusion member attached to a push wire and having a plurality of self-expanding struts with an angular cross-sectional profile, wherein a point of the profile faces outward from the clot-capturing reperfusion member; and a microcatheter for housing the clot-capturing reperfusion member, wherein relative movement between the pushwire and the microcatheter in one direction unsheathes the member, causing the member to expand, and wherein relative movement between the pushwire and the microcatheter in the opposite direction re-sheathes the member, allowing the member to retract. In aspect, the system for achieving and modulating reperfusion may include a flow modulation member capable of blocking blood flow; a pushwire with a self-expanding clot-capturing reperfusion member attached toward the distal end, and, a pushwire, adapted to be introduced to the vasculature through the microcatheter and wherein both the clot-capturing reperfusion member is attached to the pushwire; and the flow modulation member is also attached to the pushwire; and a microcatheter adapted to receive at least a portion of the pushwire, wherein relative motion between the guidewire and the microcatheter in one direction is capable of unsheathing both the flow modulation member and the clot-capturing reperfusion member, causing one or both members to expand, and wherein relative motion between the guidewire and the microcatheter in an opposite direction is capable of re-sheathing one or both of the flow modulation member and the clot-capturing reperfusion member, causing one or both members to retract.

A system for achieving and modulating reperfusion of a vessel in the cerebral vasculature following ischemic stroke is another aspect of the invention. In this embodiment, the system includes: a flow modulation member capable of reversibly reducing blood flow; a mechanism for selectively causing blood flow of the vessel to increase; and the flow modulation member adapted to reach the location of the clot via the endovasculature; the system adapted so that the flow modulation member is capable of performing at least two iterations of reducing and then varying flow in the vessel proximate the site of the clot.

A method for modulating blood flow is another aspect of the invention. In this embodiment the method includes: inserting a microcatheter into a blood vessel; inserting a pushwire into the microcatheter, wherein a flow modulation member is attached to the pushwire, wherein the member has a plurality of self-expanding struts and a membrane capable of blocking blood flow; translating the pushwire or the microcatheter relative to one another in one direction to unsheathe the member, allowing the member to expand; translating the pushwire or the microcatheter relative to one another in an opposite direction to re-sheathe the member, causing the member to retract; and repeating the translating steps at least once to modulate blood flow.

An embodiment of the invention can also be described as method for modulating blood flow for the treatment of ischemic stroke. In this embodiment the method includes: inserting a microcatheter and a fluid conduit into a blood vessel, wherein the conduit is flexible and contiguous with the microcatheter, wherein a flow modulation member is attached to the microcatheter, and wherein the member has an inflatable balloon capable of blocking blood flow; conducting inflation fluid to the balloon, causing the balloon to expand; conducting inflation fluid from the balloon, causing the balloon to retract; and repeating the conducting steps at least once to modulate blood flow.

Another embodiment of the invention can be described as a method for removing a blood clot or embolus, the method includes the steps of: inserting a microcatheter into an occluded blood vessel; inserting a pushwire into the microcatheter, wherein a self-expanding reperfusion member is attached to the guidewire and has a plurality of self-expanding struts with an angular cross-sectional profile, wherein a point of the profile faces outward from the member toward the clot or embolus; translating the guidewire or the microcatheter relative to one another in one direction to unsheathe the member, causing the member to expand to engage the clot or embolus.

The invention presently disclosed in one embodiment is a method for achieving and modulating reperfusion, the method according to this embodiment includes the steps of: inserting a microcatheter into an occluded blood vessel; inserting a pushwire into the microcatheter, wherein both a flow modulation member capable of blocking blood flow and a self-expanding reperfusion member are attached to the pushwire; translating the pushwire or the microcatheter relative to one another in one direction to unsheathe one or both of the flow modulation member and the reperfusion member, causing one or both members to expand; and translating the guidewire or the microcatheter relative to one another in an opposite direction to re-sheathe one or both of the flow modulation member causing the flow modulation member to retract; and repeating the translating steps at least once to treat an occlusion and modulate reperfusion.

The present invention in another embodiment is a method for achieving and modulating reperfusion, the method includes the steps of: inserting a microcatheter into an occluded blood vessel; inserting a pushwire into the microcatheter, wherein a self-expanding reperfusion member is attached to the guidewire; and a flow modulation member capable of blocking or reducing blood flow is attached to the microcatheter; translating the pushwire or the microcatheter relative to one another in one direction to unsheathe the reperfusion member, causing the reperfusion member to expand; and performing an expansion step to cause the flow modulation member to occlude or lessen flow; and repeating the expansion at least once to modulate reperfusion.

Finally, the present invention in an embodiment is a system for achieving and modulating reperfusion, the system includes: three catheters where in at least one region, a narrow catheter is inside an intermediate catheter, and the intermediate catheter, is inside a largest catheter; wherein a pusher member is at least partially inside the narrow catheter; and the intermediate catheter has a flow modulation member capable of reversibly occluding or blocking flow near its distal end; a reperfusion member; a pushwire, wherein the reperfusion member is attached to the pushwire; wherein relative translation between the pushwire and the smallest catheter in one direction is capable of unsheathing the reperfusion member, causing the capture member to expand.

The details of one or more embodiments of the present invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the present invention will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention and the following detailed description of certain embodiments thereof may be understood with reference to the following figures:

FIGS. 1A-1B illustrate endoluminal assemblies with a balloon and sealing ring in accordance with some embodiments of the present invention. In FIG. 1B the sealing ring is in a manner that allows the balloon to be deflated;

FIG. 2 illustrates a pushwire with a tapered distal end in an endoluminal assembly in accordance with some embodiments of the present invention;

FIGS. 3A-3B are an isometric view and a detail view, respectively, of a sealing ring system in accordance with some embodiments of the present invention;

FIGS. 4A-4D and 5 illustrate methods of using a sealing ring system with a single-lumen balloon catheter in accordance with some embodiments of the present invention;

FIG. 6 illustrates a sealing ring with a conical shape and a microcatheter with a matching distal tip in accordance with some embodiments of the present invention;

FIGS. 7A-7B illustrate alternative catheter distal tip designs for preventing a sealing ring from advancing beyond the distal tip of a catheter in accordance with some embodiments of the present invention;

FIG. 8A is a side view of an aperture in the catheter for inflating a balloon according to some embodiments of the present invention, and FIG. 8B is a sectional view taken along sectional line 8B-8B of FIG. 8A;

FIG. 9 illustrates an alternative passage shape designed for the flow of inflating fluid between the lumina of a catheter and an inflatable flow modulation member in accordance with some embodiments of the present invention;

FIGS. 10A-10B are process flow charts for performing postconditioning in accordance with some embodiments of the present invention:

FIGS. 11A-11B illustrate a sectional view of a catheter and a detail section view, respectively, of a scaling member which is constructed using an electro active polymer when the sealing member is in an unexpanded state;

FIGS. 11C-11D illustrate a sectional view of a catheter and a detail sectional view, respectively, of a catheter with a sealing member constructed using an electro active polymer according to an embodiment of the present invention when the sealing member is in the expanded state:

FIGS. 12A-12B are process flow charts for performing postconditioning in accordance with some embodiments of the present invention.

FIG. 13 illustrates a cross sectional view with a sealing ring system with an intermediate balloon catheter in accordance with some embodiments of the present invention;

FIGS. 14A-14B are process flow charts for performing postconditioning in accordance with some embodiments of the present invention;

FIGS. 15A-15B illustrate cross-sectional views of an alternative embodiment of the present invention using an electro active polymer, which constricts around the inner microcatheter according to the present invention in the constrained and open configurations, respectively;

FIGS. 16A-16B are process flow charts for performing postconditioning in accordance with some embodiments of the present invention;

FIGS. 17-18 illustrate alternative sealing tip designs for assemblies with a single-lumen balloon catheter in accordance with some embodiments of the present invention;

FIGS. 19A-19B are process flow charts for performing postconditioning in accordance with some embodiments of the present invention;

FIGS. 20A-20B illustrate cross-sectional views of assemblies with a double-lumen balloon microcatheter in accordance with some embodiments of the present invention;

FIGS. 20C-20E illustrate cross-sectional views of various microcatheters of varying numbers of lumina in accordance with some embodiments of the present invention;

FIGS. 21A-21B illustrate a process flow chart for performing postconditioning in accordance with some embodiments of the present invention;

FIGS. 22A-22B illustrate perspective views of assemblies with a double-lumen balloon catheter in accordance with some embodiments of the present invention;

FIGS. 23A-23B are process flow charts for performing postconditioning in accordance with some embodiments of the present invention

FIGS. 24-25 illustrate alternative designs for a multiple lumen balloon catheter in accordance with some embodiments of the present invention;

FIGS. 26A-26B are process flow charts for performing postconditioning in accordance with some embodiments of the present invention

FIGS. 27A-27C illustrate different views of assemblies with an umbrella-like flow modulation member in accordance with some embodiments of the present invention;

FIG. 28 is a view parallel to the central longitudinal axis of an umbrella-like flow modulation member supported by a lattice strut structure in accordance with some embodiments of the present invention;

FIG. 29 illustrates an embodiment of an umbrella-like flow modulation member supported by six primary struts in accordance with some embodiments of the present invention;

FIG. 30 is a view perpendicular to the central longitudinal axis of an umbrella-like flow modulation member supported by six primary struts in accordance with some embodiments of the present invention;

FIGS. 31A-31D illustrate alternative strut curvatures of an umbrella-like flow modulation member in accordance with some embodiments of the present invention;

FIGS. 32A-32B illustrate the angle between the central longitudinal axis and a primary strut axis in an umbrella-like flow modulation member during working and resting states in accordance with some embodiments of the present invention;

FIGS. 33A-33E illustrate various embodiments of primary strut cross sections with different shapes and dimensions in accordance with some embodiments of the present invention;

FIGS. 34A-34D illustrate various embodiments of flow modulation members with different methods of attaching the struts to a pushwire in accordance with some embodiments of the present invention;

FIGS. 35-36 illustrate various embodiments of an umbrella-like flow modulation member supported by primary and secondary struts from a view perpendicular to the central longitudinal axis in accordance with some embodiments of the present invention;

FIG. 37 is a cross-sectional view perpendicular to the central longitudinal axis of an umbrella-like flow modulation member, with its primary struts covered by a membrane having a reinforced distal edge, in accordance with some embodiments of the present invention;

FIGS. 38A-38B illustrate an umbrella-like flow modulation member having a secondary strut with a zigzag configuration around the longitudinal axis in accordance with some embodiments of the present invention;

FIG. 39 illustrates an umbrella-like flow modulation member having primary struts encased within the membrane in accordance with some embodiments of the present invention:

FIG. 40 illustrates an embodiment of an umbrella-like flow modulation member, with its primary struts encased within a membrane having a reinforced distal edge, from a cross-sectional view perpendicular to the central longitudinal axis in accordance with some embodiments of the present invention;

FIGS. 41A-41G illustrate various views of an embodiment of an umbrella-like flow modulation member, with its primary struts covered by the membrane, in accordance with some embodiments of the present invention;

FIGS. 42A-42D and 43 illustrate an embodiment of an umbrella-like flow modulation member, with its primary struts encased within the membrane, from various angles in accordance with some embodiments of the present invention;

FIG. 44 illustrates an embodiment of an umbrella-like flow modulation member with its primary struts covered on the outer side by the membrane in accordance with some embodiments of the present invention;

FIGS. 45A-45C illustrate alternative designs for a flow modulation member accordance with some embodiments of the present invention;

FIGS. 46A-46C and 47A-47B illustrate various embodiments for combining clot capture and flow modulation functionalities within the same member in accordance with some embodiments of the present invention;

FIG. 48A-48B are process flow charts for performing postconditioning in accordance with some embodiments of the present invention:

FIGS. 49A-49B are a cross-sectional view and a detail sectional view, respectively, of an embodiment of a flow modulation member in accordance with some embodiments of the present invention;

FIGS. 50A-50B illustrate a process flow chart for performing postconditioning in accordance with some embodiments of the present invention;

FIGS. 51A-51C and 52 illustrate alternative designs of a reperfusion member in accordance with some embodiments of the present invention:

FIG. 53 illustrates a reperfusion member with radiopaque material lengthwise in accordance with some embodiments of the present invention:

FIG. 54 illustrates a reperfusion member with a hexagonal cell structure in accordance with some embodiments of the present invention;

FIGS. 55A-55D illustrate alternative cell shapes for a reperfusion member in accordance with some embodiments of the present invention:

FIGS. 56-57 are alternative two-dimensional cell patterns for a reperfusion member, depicted as developed surfaces, in accordance with some embodiments of the present invention;

FIG. 58 illustrates reperfusion member struts with increased surface area in accordance with some embodiments of the present invention;

FIGS. 59A-59K are cross-sectional views of alternative strut designs for a reperfusion member in accordance with some embodiments of the present invention;

FIGS. 60A-60B are three-dimensional views of reperfusion member struts with a triangular cross-section in accordance with some embodiments of the present invention;

FIG. 61A-61F illustrate steps for deploying a reperfusion member and flow modulation member in accordance with some embodiments of the present invention; and

FIGS. 62A-62J are postconditioning schedules to illustrates various embodiments of alternative timed intervals of occlusion i/reperfusion cycles for flow modulation in accordance with some embodiments of the present invention.

DETAILED DESCRIPTION

Embodiments of the present invention include methods for preventing, treating, and/or at least minimizing ischemic stroke and/or reperfusion injury by restoring and/or modulating blood flow, particularly in the cerebral vasculature. The methods, generally referred to as postconditioning are performed with devices and systems, which are adapted for use in the performance of the controlled restoration and/or modulating of blood flow. The devices, systems, and methods described herein make it possible for a clinician to adequately and systematically restore blood flow to ischemic tissue while simultaneously modulating the blood flow to minimize reperfusion injury. Some embodiments of the present invention specifically enable postconditioning in the challenging dimensional constraints of the brain. Some embodiments further enable improved binding with clots and reperfusion by creating an increase within the cross-sectional area between the clot and the blood vessel wall or in the clot itself, particularly for clots that are resistant to the weak engagement of existing thrombectomy devices and/or systems. Contributing features, such as flexibility and radial force, will be discussed further herein.

As used herein, “proximal” indicates a direction closer to the entry point of the catheter. “Distal” indicates a direction further away from the entry point. Moreover, distal and proximal refer to regions either on the device as a whole or on a specific component and thus designate relative position rather than a fixed point. The term cross-sectional “diameter” does not necessarily imply a circular shape with respect to a cross-section of, for example, a balloon with an elliptical cross-section Diameter can also refer to the longest dimension of a cross-section of a component of any shape, including, but not limited to ellipsoids, ovoids, polygons and any path-connected volume.

A “seal” or an object adapted for blocking (“sealing”) an opening, such as a sealing ring or sealing tip for sealing a catheter lumen, may completely or partially block fluid passage from one or both sides of the seal. Additionally the seal may increase resistance to flow or decrease the volumetric rate of fluid passing through the opening. Likewise, an object adapted for “occluding” flow in a passage may completely or partially block flow or at least increase resistance to flow or decrease the volumetric rate of a substance passing through the passage. A clot-capturing reperfusion member is an apparatus that achieves at least partial reperfusion of an occluded artery while attempting capture or partial capture of the clot. A flow modulation member is a device that is suitable to regulate and control the flow of blood, after the occlusion has been partially or completely resolved.

Reperfusion and/or Flow Modulation Devices and Systems

According to some embodiments of the present invention, a flow modulation system may include an initial guidewire, a microcatheter, an intermediate catheter, and/or a flow modulation member. According to some embodiments of the present invention, a reperfusion system may include an initial guidewire, a microcatheter, an intermediate catheter, a pushwire and/or a reperfusion member. In further embodiments of the present invention, a flow modulation system and a reperfusion system may be combined to systematically and effectively control the restoration of blood flow so as to prevent, minimize, and/or treat ischemic stroke and/or reperfusion injury by restoring and modulating blood flow in a blood vessel, such as an cerebral artery.

FIGS. 1A-B, for example, illustrate endoluminal assemblies in accordance with some embodiments of the present invention. The assembly in FIG. 1A, which is disposed in a blood vessel with a wall 114, includes an inflated flow modulation member 100, a microcatheter 102, a pushwire 106, and a reperfusion member 108 that is attached to the pushwire with an attachment ring 110. The pushwire 106 is an example of the variety of “wires” that may be used to implement the embodiments of the present invention. These devices are situated within the luminal wall 114 of a blood vessel (only one wall is illustrated) with blood flowing from the proximal direction 116 to the distal direction 118. FIGS. 1A-1B also illustrate, to be described below in accordance with some embodiments, a sealing ring 104, a narrowed portion b of a microcatheter 120, wherein the space in the catheter lumen, between the pushwire 106 and the luminal wall of the microcatheter 102 decreases 120 from proximal luminal space 126 to distal luminal space 128, an inflation fluid passage 122, a radiopaque marker 124, and an attachment region 130 to attached the flow modulation member's membrane to the catheter. FIG. 1B shows the flow modulation member deflated, in a configuration that is more permissive to flow. FIG. 2 illustrates a pushwire 106 with a tapered distal end leading to an endoluminal assembly 108 in accordance with some embodiments of the present invention

According to some embodiments of the present invention, an initial guidewire or access wire may be included and used to navigate an initial path through the vasculature from a point of insertion into the body (located, e.g., at the groin) to a location in a blood vessel of a clot and/or ischemic region (e.g., a cerebral artery). A guidewire may be advanced beyond the clot and/or ischemic region to allow sufficient clearance for catheters and devices to advance through the vessel in accordance with embodiments of the present invention.

According to some embodiments of the present invention, a guidewire may be manufactured from one or more materials including, but not limited to, gold, nitinol, platinum, stainless steel, nickel, titanium, and tungsten. In some embodiments, a guidewire may be plated with radio-opaque materials, such as gold or platinum, to aid visibility during a procedure. In further embodiments, a guidewire may have some form of exterior coating to reduce friction and/or provide other advantages. Exterior coatings may include, but are not limited to, a silicone coating to reduce friction, a hydrophilic coating to lubricate, an anti-thrombogenic/Heparin coating to inhibit clotting, a hydrophobic coating to provide greater tactile response, and a polytetrafluoroethylene (PTFE) coating to reduce friction.

According to some embodiments of the present invention, one or more catheters or flexible tubes may be inserted and used to deliver devices and/or fluids to the clot and/or ischemic region. According to some embodiments, a catheter may have one or more lumina. A catheter may be advanced over the inserted guidewire, which enables the catheter to follow its predefined pathway to the point of treatment. According to some embodiments, “catheters” may include, but is not limited to, a microcatheter, an intermediate catheter, and a larger catheter (the “larger” designation refers to the size of the catheter relative to the other catheters. While portions of the specification may refer to a “large” catheter, the references should be interpreted from the perspective of the other catheters used in conjunction with the invention described herein.

According to some embodiments of the present invention, a microcatheter may be used to deliver devices and/or fluids to the clot and/or ischemic region of the blood vessel. These devices and fluids may include, but are not limited to, flow modulation members, reperfusion members, inflating fluids, and medications (e.g., tPA).

According to some embodiments of the present invention, an intermediate catheter (e.g., size 5 French) may be used to establish a conduit to a position closer to the clot and/or ischemic region of the blood vessel, preserve a path to the clot, and/or decrease the time needed for multiple passes. An intermediate catheter may be used to deliver devices and/or fluids including, but not limited to, microcatheters, flow modulation members, reperfusion members, inflating fluids, and drugs (e.g., tPA). An intermediate catheter may also be used to contain or aspirate clot material once a reperfusion member is pulled into the catheter.

According to some embodiments of the present invention, a large catheter (e.g., size 6 French, such as ENVOY® Guiding Catheter available from DePuy Orthopedics, Inc. (Warsaw, Ind.)) may be used to establish a conduit for the guidewire and catheters through larger blood vessels, preserve that path, and decrease the time needed for multiple passes. A larger catheter may also be used to contain or aspirate clot material once a reperfusion member is pulled into the catheter.

According to some embodiments of the present invention, a catheter may be manufactured from materials including, but not limited to, silicone rubber, nitinol, nylon, polyurethane, polyethylene terephthalate (PETE) latex, and thermoplastic elastomers. In further embodiments, catheters may have some form of exterior or interior coating to reduce friction, lubricate, inhibit clotting, provide greater tactile response, and/or provide other advantages. Coatings may include, but are not limited to, a silicone coating to reduce friction, a hydrophilic coating to lubricate, an anti-thrombogenic/Heparin coating, a hydrophobic coating, and a PTFE coating. The interior and/or exterior surface of any of the catheters described in this invention may include a material or treatment to reduce friction.

Following removal of an initial guidewire, a pushwire may be inserted into a lumen of a microcatheter that has been placed over the initial guidewire in accordance with embodiments of the present invention. This “pushwire” carries one or more distal devices, such as a flow modulation member and a reperfusion member. A pushwire may be inserted and guided along a predefined pathway to the location of a clot and/or ischemic region in the body to deliver distal devices, generally by translation. According to some embodiments, when a microcatheter is retracted, a distal device on the pushwire may be unsheathed by translation of the microcatheter in the proximal direction. In further embodiments, a distal device on the pushwire may be resheathed by translation of the microcatheter into an intermediate catheter. A pushwire may taper toward the distal end to provide more latitudinal flexibility and room for distal devices. FIG. 2 illustrates a guidewire 106 with tapering in region 200 in accordance with some embodiments of the present invention. In addition to the distally tapered pushwire 106, FIG. 2 illustrates a sealing ring 104 between the pushwire 106 and a microcatheter 102, and a clot capture member 108 that is attached to the pushwire 106 with an attachment ring 110. In preferred embodiments, the diameter of a pushwire is about 0.010 inches. However, pushwires with diameters ranging from approximately 0.008 inches to 0.018 inches may be used.

According to some embodiments of the present invention, a pushwire may be manufactured from one or more materials including, but not limited to, gold, nitinol, platinum, stainless steel, nickel, titanium, and tungsten. In some embodiments, a pushwire may be plated with radio-opaque materials, such as gold or platinum, to aid visibility during a procedure. In further embodiments, a pushwire may have some form of exterior coating to reduce friction and/or provide other advantages. Exterior coatings may include, but are not limited to, a silicone coating to reduce friction, a hydrophilic coating to lubricate, an anti-thrombogenic/Heparin coating to inhibit clotting, a hydrophobic coating to provide greater tactile response, and a PTFE coating to reduce friction.

According to some embodiments, a delivery handle and winged steering apparatus, which remain outside the body, may be used to facilitate the insertion and/or control the movements of guidewires, catheters, pushwires, and distal devices, by allowing an operator to impart greater torque.

According to some embodiments of the present invention, a reperfusion member is any mechanical device or chemical entity adapted to achieve reperfusion. A clot-capturing reperfusion member is a type of reperfusion device that engages with a clot in a blood vessel, with the goal of removing the clot (preferably from the body entirely) in accordance with some embodiments. In some embodiments, a clot-capturing reperfusion member may be a distal device, that is, the clot-capturing reperfusion member may be coupled to the distal end of a pushwire and delivered to the location of a clot via the lumen of a catheter. A pass is an attempt to macerate, dislodge, and/or remove clot material. According to some embodiments, a pass may consist of navigating a guidewire past the location of a clot, translating a catheter over the guidewire and past the clot, exchanging the guidewire for a pushwire coupled with a reperfusion member, such as a clot-capturing reperfusion member. If a first pass is not successful, a new pass may require repeating one or more of these steps. Reperfusion members generally and improved variations thereupon are described in greater detail elsewhere herein in accordance with some embodiments of the present invention. Reperfusion members whose function is to restore flow in a blood vessel are included in a larger group of flow restoration members. Both reperfusion members and flow restoration members may have a variety of configurations suitable for the purpose of the present invention.

According to some embodiments of the present invention, a flow modulation member is any device adapted to modulate blood flow by, for example, reversibly occluding a blood vessel. A flow modulation member may partially or completely occlude a blood vessel, for example, in intervals, with the goal of postconditioning an ischemic region, particularly to prevent and/or minimize reperfusion injury, in accordance with some embodiments. In some embodiments, a flow modulation member may be a distal device, that is, the flow modulation member may be coupled to the distal end of a pushwire and delivered to the location of a clot via the lumen of a catheter. In other embodiments, a flow modulation member may be an inflatable member that is coupled to the distal end of a pushwire, a microcatheter, or an intermediate catheter.

For embodiments in which a flow modulation member inflates and deflates to reversibly occlude a blood vessel, a lumen of a catheter may be used as a conduit for inflating fluid. In some of these embodiments, a port may be added to the proximal end of the catheter for pumping the inflating fluid. Other ports may be provided for inserting other fluids and devices, such as a probe for monitoring pressure in the inflatable member. Flow modulation members generally and improved variations thereupon are described in greater detail elsewhere herein in accordance with some embodiments of the present invention.

According to some embodiments, a flow modulation member is positioned proximal to a clot and/or reperfusion member in order to reversibly control occlusion at the same time that a reperfusion member is first engaged with a clot to begin reperfusion. A flow modulation member should be positioned close to the clot and/or reperfusion member to minimize the probability of interference with from a collateral artery feeding the reperfused blood vessel between the flow modulation member and the clot, but not so close as to disturb the clot or reperfusion member. In preferred embodiments, the proximity of a flow modulation member is selected to maximize the extent to which a reperfused blood vessel receives the benefits of postconditioning. For example, in the embodiments shown in FIGS. 1A-1B, the flow modulation member 100 is designed with a balloon of 2.4 mm diameter (at its target level of inflation) for blood vessels with a diameter of 2 mm, and is positioned so that the location the center of the balloon is 12 mm proximal to the distal end of the microcatheter. The distance between the center of the balloon and the distal end of the microcatheter may range from 5 mm to 40 mm.

Single-Lumen Balloon Embodiments of a Flow Modulation Member

According to some embodiments of the present invention, the flow modulation member consists of an expandable membrane (“balloon”), which may have some features similar to balloons used for cardiac postconditioning and/or balloon catheters. However, one critical difference between the present embodiments and balloons used in other parts of the body is that this flow modulation balloon and its inflating-fluid conduit must be able to navigate the narrow, winding blood vessels of the brain. Existing inflatable tube configurations (which may, for example, be inflated with saline solution), particularly those that may be used in connection with a clot treating system, are not capable of effectively reaching the parts of blood vessels where clots tend to occur. Thus, embodiments are designed to overcome the obstacles of size and flexibility while maintaining the ability to inflate and deflate rapidly, as controlled by an operator or programmable device.

Single-Lumen Balloon Microcatheters with Pushwire-Bearing Sealing Rings

FIGS. 1A-1B and 3A-3B illustrate unique assemblies, in accordance with some embodiments of the present invention, including a sealing ring 104 mounted on a pushwire 106 and a balloon 100 mounted on a microcatheter 102 at attachment regions 130. The configurations provide enhanced navigability and allows for the delivery of the reperfusion member 108 at the location of the clot. Clots tend to lodge in the Middle Cerebral Artery, where the vasculature is particularly tortuous. Current single-lumen balloon microcatheters cannot be used to deliver stent-based reperfusion members because their mode of action is incompatible with stent delivery. Current single-lumen balloon microcatheters have a seal at the distal end that exactly fits the diameter of the appropriate guidewire. Therefore, the distal seal on current single lumen balloon microcatheters would interfere with stent-based reperfusion members attempting to exit the microcatheter's distal end. Narrow catheters, of which microcatheters are an example, are also suitable for implementing the embodiments of the present invention.

The sealing ring 104 assembly, positioned at the distal end of the pushwire 106, before the reperfusion member 108 (i.e., with distance a between the sealing ring 104 and the attachment ring 110 for the reperfusion member 108), allows for a reperfusion member to be compatible with a balloon microcatheter. The sealing ring 104 allows for a sealing at narrower region b with increased diameter, so that the reperfusion member 108 has ample space to pass through the sealing region without risking jamming the assembly. The ring completes the seal upon entering the sealing region b. Therefore the sealing ring 104 enables the narrow sealing region b to be wider than the diameter of the pushwire.

The preferred length of the sealing ring is approximately 2 mm. However, different dimensions for the sealing ring may be used (e.g., from approximately 1 mm to 5 mm in length). The diameter of the sealing ring is preferred to be the same as the inner diameter of the narrower region b of the microcatheter (toward the distal end). It is anticipated that matching diameters will provide adequate sealing while minimizing the risk of assembly jamming. However, different dimensions for the sealing ring may be used (e.g. from 0.010″ to 0.030″ in diameter).

The sealing ring can be attached to the pushwire in many ways. The preferred method is swaging. Other methods that may be used include, but are not limited to, interference fitting and soldering. In the preferred embodiment, the sealing ring is composed of the same material as that of the pushwire. This material is preferred to be stainless steel, although other materials, such as platinum-tungsten alloys, may be used.

There are numerous ways that a sealing ring on the pushwire can be used to create a seal that will permit the reperfusion member to pass through as well as facilitate postconditioning. The embodiments above are only examples.

The preferred embodiment is a microcatheter with a single-walled balloon operated in conjunction with a pushwire-bearing a sealing ring. The cross-sectional profile of the microcatheter narrows 120 at the distal end, such that when the microcatheter is mounted on the pushwire, the sealing ring creates a seal when the sealing ring is in the narrower region b of the microcatheter.

A double lumen catheter, having a separate lumen for the inflating fluid, would not need a seal around the surface of the pushwire. The second lumen for the balloon-inflating fluid would be within the walls of the microcatheter itself. Even without supports (e.g. in a floating double lumen design), both tubes are advanced simultaneously making the entire assembly more rigid.

The sealing ring allows for the saline solution, pushwire, and reperfusion member to share a single lumen. In the embodiment shown in FIGS. 1A, 1B, 3A, 3B there is space 126 between the pushwire 106 and the luminal wall of the microcatheter 102 to allow the inflating solution to travel through the lumen of the catheter 102, through inflation passages 122, and into the lumen of the flow modulation member 100 to inflate the balloon. The space 126 is identified in FIGS. 1A and 1B. Additionally, this space 126 ensures reduced friction between the reperfusion member and the microcatheter, during the translation of one with respect to the other. The sealing ring 104 is positioned proximally to the reperfusion member 108. The balloon microcatheter has a double lumen, at the locus of the balloon 100 (the membrane of the balloon being a lumen)—but a single-luminal wall everywhere else. The inner lumen of the microcatheter 102 bears inflating holes 122 (two holes in the embodiment shown) that connect the lumen of the balloon to the inner layer, to let the inflating fluid reach the cavity of the balloon. When translated into the narrower portion of the microcatheter, the sealing ring creates a seal that prevents the saline solution from flowing past the sealing ring 104 and freely out of the distal end of the microcatheter. Once the sealing ring 104 is advanced into the narrower portion b of the microcatheter, pumping solution through the proximal end of the microcatheter will result in the inflation of the balloon.

As noted previously, in some embodiments the sealing mechanism is mounted on the pushwire and not protruding from the inner wall of the catheter. If the sealing member were mounted on the microcatheter, the reperfusion member would need to pass through the seal and might become jammed in the process. In other words in order to prevent the inflating solution from flowing out the distal end of the microcatheter, the lumen of the microcatheter would need to be flush with the pushwire, at some location distal to the balloon. This seal around the pushwire would interfere with the translation of the reperfusion member.

The sealing ring is preferred to be rounded on both the proximal and distal ends to promote ease of entering the narrower portion of the microcatheter as well as re-entering the microcatheter. The sealing ring would only need to re-enter the microcatheter if the microcatheter is retracted too far in the proximal direction (e.g., beyond the proximal end of the sealing ring) from the reperfusion member during the procedure. However, it is suggested that the microcatheter cover the sealing ring at all times. That is the operator should not pull the microcatheter proximally to the extent that the distal 118 end of the microcatheter is proximal to the sealing ring 104.

The diameter of the distal end of the microcatheter does not widen in some embodiments (although in other embodiments this might make it easier for the sealing ring to backer-enter the microcatheter, should it fall out) because such a widening of the distal end of the microcatheter would hamper navigability of the microcatheter.

The preferred diameter shown of the pushwire is about 0.010″. However, pushwires with diameters ranging from about 0.008″ to about 0.018″ may be used.

Microcatheters Compatible with Pushwire-Bearing Sealing Rings

In the preferred embodiment, the inner diameter of the microcatheter 102 (excluding the narrower region b at the tip) is greater than the diameter of the sealing ring 104.

The inner diameter throughout the microcatheter may be the same as the diameter of the sealing ring; however, this is not the preferred embodiment.

Increasing the inner diameter of the microcatheter 102 slightly, in the preferred embodiment, will serve to prevent the inflating fluid from being pushed forward by the sealing ring 104 (e.g., such as in a plunger-barrel assembly) because inflating fluid will be able to travel freely around the sealing ring, at times when the sealing ring is not within the sealing region. Importantly for some embodiments, having the majority of the inner diameter of the microcatheter 102 be greater than the diameter of the sealing ring 104 can serve to reduce friction between the microcatheter and the sealing ring. This friction could be meaningful given that the sealing ring 104 would encounter it throughout its journey through the microcatheter 102 and especially given the tortuous curves that the assembly will take. The microcatheter 102 will have this sufficient diameter from the proximal end until near the distal end, where the diameter narrows (shown at reference numeral 120) to the size of the sealing ring 104 so that a seal can be created.

In FIGS. 1A, 1B, 3A and 3B, the inner lumen of the microcatheter 102 narrows at the tip. This creates a seal only when the sealing ring 104 is within the narrowed portion b of the lumen. The narrowed region b may be at the last few centimeters of the tip, start from after the inflating holes 122, or in the last centimeter from the distal end. A slightly longer narrowed region b provides for greater position flexibility for the microcatheter 102 (relative to the clot) while being able to operate the balloon 100.

In a preferred embodiment the length of the sealing area b—the portion of the microcatheter 102 that is narrower and thereby creates a seal when the sealing ring 104 is inside—is less than the length of the pushwire 106 between the distal end of the sealing ring and the proximal end of the reperfusion member 108. This allows for the reperfusion member to be fully released, while permitting the operator the option to selectively have a seal or not have a seal. Without a seal, a bolus of contrast agent can be injected through the microcatheter 102 and be released through the distal end of the microcatheter. Compounds to facilitate clot removal, accelerate healing of the blood vessel, minimize reperfusion injury etc. may be delivered through the lumen of the microcatheter 102 to the area of the clot/infarct region. When the seal is made, the balloon 100 can be inflated. An additional constraint/consideration is that the distance between the balloon 100 and the reperfusion member 108 should be short in order to minimize the chance of interference by a collateral artery during postconditioning. If another blood vessel were to intersect the occluded artery, between the clot and the balloon, then the balloon 100 would not be able to cut off blood supply entirely during postconditioning. In other words, the collateral blood vessel would not be blocked and would continue supplying blood to the region even when the balloon was fully inflated. In the preferred embodiment shown, the distance a is approximately 8 mm and the distance b is approximately 5 mm.

Specifications follow for the preferred embodiment shown in FIGS. 1A, 1B, 3A and 3B. However, a range of specifications and dimensions may be used.

The wall thickness of the microcatheter 102 is about 85 μm.

In the wider part of the microcatheter 102, the gap 126 between the pushwire 106 and the inner lumen of the microcatheter—if the pushwire is centered within the microcatheter—is about 150 μm. However, this gap 126 may range from approximately 50 μm to 300 μm.

The inner diameter of the wider portion of the microcatheter 102 is approximately 0.018″. However microcatheters having a range of diameters, for example, approximately 0.014″ to 0.021″ may also be used. In the narrower part b of the microcatheter, the gap 128 between the pushwire and the inner lumen of the microcatheter—if the pushwire is centered within the microcatheter—is about 100 μm. However, this gap may range from about 30 μm to about 280 μm. The preferred inner diameter of the narrower portion of microcatheter is approximately 0.002″less than the inner diameter of the wider portion of microcatheter. Extrusion is the preferred method to manufacture the microcatheter.

FIGS. 4A-4D illustrate steps for using assemblies with a single-lumen balloon microcatheter and a pushwire-mounted sealing ring in accordance with some embodiments of the present invention. The assembly in FIGS. 4A-4D includes a flow modulation member balloon 100 deflated and flush against the outer wall of the microcatheter 102 with inflating fluid passages 122. When the sealing ring 104 is in a first region 400 of the microcatheter 102, the balloon 100 cannot inflate, fluid can flow through the microcatheter and into the blood vessel, and the clot-capturing reperfusion member 108 is constrained, as shown in FIG. 4A. When the microcatheter is translated proximally 116 so that the sealing ring is in a second region 402 of the microcatheter, the balloon 100 cannot inflate, fluid can flow through the microcatheter 102 and into the blood vessel, and the clot-capturing reperfusion member 108 is partially constrained, as shown in FIG. 4B. When the microcatheter 102 is translated further proximally so that the sealing ring 104 is in a third region 404, the balloon 100 cannot inflate, fluid can flow through the microcatheter 102 and into the blood vessel, and the clot-capturing reperfusion member 108 is fully deployed, as shown in FIG. 4C. When the microcatheter 102 is translated even further proximally so that the sealing ring is in fourth region 406, the balloon can inflate, as shown in FIG. 4D.

FIGS. 10A and 10B, 12A and 12B, 14A and 14B, 16A and 16B, 19A and 19B, 21A and 21B, 23A and 23B, 26A and 26B, 48A and 48B and 50A and 50B describe in detail the steps for using the assemblies disclosed in the present specification in connection with different embodiments of the present invention. As illustrated in FIG. 5, while the sealing ring 104 is in the narrower region of microcatheter 102, inflating fluid 500 can be pumped into the microcatheter and will inflate the balloon 100. In this alignment of elements, as shown in FIG. 5, fluid will not freely pass from the microcatheter into the blood vessel, and the clot-capturing reperfusion member is fully deployed. Additionally, various ports, connectors (such as Luer locks) and adaptors can be used at the proximal end of the catheter in a manner enables the device to deliver fluid in accordance with the present invention.

This slightly wider microcatheter also creates an ideal channel to deliver fluids to the infarcted tissue in region of the clot and/or the clot itself (e.g., contrast agent, agents to treat reperfusion injury, agents to aid in clot removal. Tissue plasminogen activator (tPA) could also be applied locally—reducing the systemic risks of bleeding—and in lower overall quantities. Agents that may minimize reperfusion injury include, but are not limited to, cyclosporine, calpain inhibitors, sodium-calcium Na+/Ca2+ exchange inhibitors, monoclonal antibodies, temperature reducing agents, or agents that slow cell metabolism. Agents that may aid in clot removal include, but are not limited to, tissue plasminogen activator and other agents that aid in dissolving, dislodging, and/or macerating clots. Agents that may otherwise benefit the patient's condition include pharmaceuticals or compounds commonly used for treating clots, preventing restenosis, intravascular device coatings (e.g., vasodilators, nimodipine, sirolimus, paclitaxel) and agents that promote the entanglement or attachment of a clot with a reperfusion member (e.g., fibronectin). The preferred embodiment will therefore provide an opportunity to use drugs that may help lessen the ischemic and reperfusion injuries and/or speed recovery.

The sealing ring may come in various shapes and dimensions. The sealing ring need not be shaped so as to resemble a cylinder with a substantially circular base. As shown in FIG. 6, the sealing ring 600 is disposed on the pushwire 106 and may be shaped as a cone in accordance with some embodiments of the present invention. In this cone shape, the sealing ring 600 may be configured to fit (either partially or fully) into a corresponding narrow section 602 of the microcatheter.

FIGS. 7A-7B illustrate, according to some embodiments, alternative microcatheter designs for preventing the sealing ring 104 from advancing beyond the distal end of the microcatheter. In both embodiments, the sealing ring 104 includes a forward (distal) end 702 and a back (proximal) end 704. In FIG. 7A, the distal end of the microcatheter 700 tapers after the sealing region as illustrated at region 712. The inside taper of the region 712 is configured to conform to the distal end 702 of the sealing member. In FIG. 7B, an additional region 706 with a diameter too narrow to permit passage of the sealing ring 104 further stabilizes the blockage, ensuring that the sealing ring will be less likely to pass through even if force is exerted. The sealing ring may be designed to not fully enter into a sealing region but instead for only the distal portion of the sealing ring to contact one or more narrowing regions of the microcatheter. The microcatheter may have either sharp or rounded edges on one or more sides, and the slope of the edges may vary. The microcatheter diameter may taper linearly, sharply, or gradually. The narrowing regions of the microcatheter need not be manufactured contiguously. For example, a tube with a smaller diameter than the microcatheter (or another ring) may be attached within the microcatheter (in effect, narrowing the lumen of a distal portion of the microcatheter). Another example is where the distal end of the balloon wraps around and into the distal end of the microcatheter to create the narrower sealing (i.e., ring stopping) portion.

Balloons Compatible with Pushwire-Bearing Sealing Rings

In all embodiments herein having a balloon, the membrane of the balloon may be constructed from various materials. Polypropylene is preferred but other materials may be used, including, but not limited to, thermoplastic polymers, elastomeric silicones, latexes, other polymers or a blend thereof (e.g., ENGAGE® polyolefin elastomers available from the Dow Chemical Company (Midland, Mich.)). To reliably occlude while not damaging the artery, the balloon is soft, compliant and operated under a range of low pressures. The balloon may occlude the vessel at inflation pressures ranging from about 0.1 to 5 atm. The balloon is preferred to be one-size-fits-all-cerebral-vessels with balloon diameters ranging from 1 to 5 mm in the inflated state. Alternatively, various microcatheters may be manufactured with balloons of different sizes to accommodate a range of occluded vessel diameters. The target diameters of the different sized balloons may be about 1 to 5 mm (i.e., different sizes are suitable for differently sized arteries). The length of the balloon is preferred to be 10 mm (which, in some embodiments can be short to improve navigability). However, a range of balloon lengths may be used (for example from about 5 mm up to about 30 mm).

The balloon may be coated with various coatings to reduce friction between the balloon and the vessel and also to avoid adhesion of thrombus. For example, a hydrophilic coating such as polytetrafluoroethylene, is preferred.

Radiopaque marker-bands 124 (illustrated in FIGS. 1A and 1B) are preferred to be placed near the horizontal extremities of the balloon. It is preferred to place two marker-bands, one near the proximal end of the balloon and one near the distal end. In embodiment of FIGS. 1A and 1B, the marker-bands 124 are around the microcatheter 102, but within the inner lumen of the balloon 100. Alternatively, the marker-bands may be embedded within the plastic wall of the microcatheter. Radiopaque materials may also be incorporated within the material of the balloon membrane, or used to coat the balloon. The radiopaque materials aid the operator in seeing the position, state of expansion, and rate of expansion and compression of the balloon. Any of these radiopaque marker configurations can be used with different disclosed embodiments. Along with saline solution, contrast agent may be part of the inflating solution so that the inflation of the balloon may be observed with angiography.

FIGS. 8-9 illustrate a passage for the flow of inflating fluid between a catheter 102 and an inflatable flow modulation member in accordance with some embodiments of the present invention. In FIG. 8, the passage, illustrated as inflating hole 122, (illustrated in FIGS. 1A, 1B, 3A, 3B) is circular 800 and has a diameter of, for example, about 100 μm. Other diameters may also be used including, but not limited to, the range of about 30 μm to 200 μm. More than one hole with similar or differently sized diameters and shapes may be used. The holes have walls 802 which may be cylindrical, but may also embody some other configuration, e.g. a tapered configuration may reduce the likelihood that the clot capture reperfusion member may snag on the hole 800. FIG. 9 illustrates an alternative embodiment, in which an elliptical inflating hole 900, so that the smallest diameter is parallel to the central axis 902 of the microcatheter 102 (so as to reduce the likelihood of the clot-capturing reperfusion member from temporarily catching on or jamming in the inflating hole). The dimensions of the inflating hole shown in FIG. 9 are about 30 μm at the smallest diameter and about 100 μm at the largest diameter. In other embodiments, the shape and/or size of the base of an inflating hole may vary. One or more inflating holes may be cut into the microcatheter or catheter using methods including, but not limited to, electron beam drilling, laser drilling, and classical machining.

The balloon 100 is attached to the microcatheter 102 in the attachment regions 130 (illustrated in FIGS. 1A, 1B, 3A, 3B) on either side of the inflating membrane. The attachment regions 130 are contiguous bands around the microcatheter 102. The attachment regions keep the inflating solution from escaping from the balloon 100. Many methods may be used to attach the balloon 100 to the microcatheter 102 (e.g., fusion bonding, ultrasonic welding, solvent bonding, induction welding, and dielectric welding).

Embodiments that utilize programmed flow modulation may be used to standardize manual work and/or to automatically detect and adjust the pressure in the flow modulation balloon to exert the desired pressure on the blood vessel walls. Pressure sensing capabilities make it easier to inflate the balloon according to the varying radii of different blood vessels. Thus, a balloon flow modulation system according to some embodiments may be more precise and responsive, may require less work and judgment on the part of an operator, and may keep detailed treatment records.

A multi-port adapter (e.g., a dual port adaptor) may be attached to the proximal end of the conduit (e.g., a balloon microcatheter) to receive the inflating fluid. The adapter has a port for the endovascular devices that can be used to access the lumen of the microcatheter, as well as a port for attaching a removable pressure transducer. The transducer is either manually operated (e.g., by a syringe) or automatically operated pump (e.g., peristaltic pump). The pressure transducer will inflate and deflate the balloon to create postconditioning (sequence of blocking and restarting blood flow).

The pressure transducer apparatus could be, for example, peristaltic pumps such as the Ismatec ICC 3 Channel 8 Roller Peristaltic Pump (available from Cole-Parmer (Vernon Hills, Ill.) or the mp6 micropump (available from Bartels Mikrotechnik GmbH, Munich, Germany). The pump should have a flow rate superior to about 5 mL-per-minute in order to inflate the balloon in less than 10 seconds.

A preprogrammed (or programmable) electronic control system is preferred to control the electronic signals that drive the flow rate or pressure differential across the transducer according the desired postconditioning protocol. This electronic control system is useful because it adds precision to the postconditioning cycles and convenience (in comparison to manual control of the expansion and deflation of each cycle). The electronic control system is preferred to be a freestanding small chip. However, various types of computers and electronics may also be used. For example, the Ismatec ICC3 Channel 8 Roller Peristaltic Pump (Cole Parmer, Vernon Hills, Ill., USA) may be linked with a computer and controlled with software such as LabVIEW (available from National Instruments, Austin, Tex., USA).

Pressure data may be collected, preferably by inserting a pressure-sensing probe (e.g., a manometer) into a separate port near the proximal end of the conduit for the inflating fluid (e.g., a balloon microcatheter). This pressure data is preferred to be processed by the electronic control system. If at any time the pressure exceeds a threshold that may compromise the mechanical integrity of the balloon or blood vessel, the electronic control system will cause the pressure transducer to remove inflating fluid from the balloon and reduce pressure.

Methods of Using Pushwire-Bearing Sealing Rings

FIGS. 10A and 10B are process flow charts for performing postconditioning with mechanical thrombectomy (an example of a technique to achieve reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIGS. 10A and 10B may be applied to assemblies with a single-lumen balloon catheter and a pushwire bearing a sealing ring.

In step 1001, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 1002, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In optional step 1003, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the larger catheter to a position distal to the location of the clot.

In step 1004, a microcatheter is inserted over the guidewire and advanced so that its distal end is positioned distal to the clot. The microcatheter has a distal region in which its internal diameter decreases. The microcatheter may, but need not, advance any further than the distal end of the guidewire. In step 1005, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a reperfusion member coupled to its distal end and a sealing ring proximal to the reperfusion member. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an active region). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 1006, the active region will expand and engage with the clot. During all passes with the clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the sealing ring coupled to the pushwire enters the narrow distal region of the microcatheter and creates a seal within the microcatheter lumen proximal to the sealing ring for retaining inflating fluid in the microcatheter.

Following step 1006, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 1007 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with postconditioning 1010 if postconditioning has not be already performed on a prior pass, or step 1011, which consists of extracting the device to move towards completion of the procedure, if postconditioning was performed previously.

In step 1006, if the blood vessel has not been sufficiently reperfused, then proceed to step 1007 where inflating fluid is pumped into the single microcatheter lumen, thus inflating the flow modulation member and occluding the blood vessel. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 1008 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1009 with the insertion of a new guidewire. Steps 1004-1009 are repeated in subsequent passes until either (1) the predetermined maximum number of passes has been completed, in which case proceed with step 1013, or (2) the blood vessel is sufficiently reperfused, in which case proceed with either step 1010 if postconditioning has not been already performed or step 1011 if postconditioning was performed previously.

Therefore, if the blood vessel is sufficiently reperfused after step 1006 or step 1007, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. To perform postconditioning, the flow modulation member (e.g., a balloon) is inflated and deflated in step 1010 according to a determined series of one or more postconditioning cycles. Preferred examples of postconditioning cycles are described in greater detail elsewhere herein.

According to some embodiments of the present invention, the balloon is inserted with, attached to, and flush with the external wall of the microcatheter. The balloon may be inflated and deflated either by manual or by automatic pumping of inflating fluid in and out of the microcatheter lumen, which is continuous with the balloon lumen via inflation holes. When inflating fluid is pumped through the microcatheter, it flows through the inflation holes in the microcatheter lumen wall and into the balloon. The balloon membrane expands against the blood vessel, blocking a substantial portion of the vessel's lumen. In a preferred embodiment, the balloon membrane contacts the inner lumen of the blood vessel to create a complete occlusion of blood flow. The balloon membrane is flexible so that it will conform to the blood vessel's wall. By having a blood-flow-occluding balloon in place, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of inflating fluid from the microcatheter, the balloon also empties (i.e., deflates) and gradually resumes its former shape, once again becoming flush with the external wall of the microcatheter. Inflating fluid can be removed using, for example, suction or by unsealing the microcatheter (via moving the sealing region away from the sealing ring). With deflation, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 1011. In a given pass, after unsheathing the clot-capturing reperfusion member in step 1006 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, with the microcatheter and pushwire, within and through the intermediate catheter (if present) and/or the larger catheter. Therefore, the intermediate and/or larger catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 1012, the operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 1012, if a sufficient amount of clot material has been retrieved, as evidenced by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 1013. However, if an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1009 with the insertion of a new guidewire.

Using Electroactive Polymers to Enable Occlusion Using Flow Modulation Member

An electroactive polymer (EAP) may be used to perform an intermediate step that allows for the flow modulation member to occlude the blood vessel. In some embodiments, the electroactive polymer is used as a controllable seal for inflating fluid. The electroactive polymer shown in FIGS. 11A-11B may be used for the sealing ring 1104. The passage of electric current through the connectors 1140 and 1142 will reversibly increase the volume of the sealing ring 1104, including its diameter. When the sealing ring expands FIGS. 11C-11D, it contacts the walls of the microcatheter 1102 and creates a seal. When using an expandable sealing ring, a narrower distal diameter 128 (shown in FIGS. 1A and 1B) for the microcatheter may not be needed.

Various electroactive polymers may be used, including, but not limited to, PPy (Polypyrrole), NAFION®, ionic polymer-metal composites (ionic EAPs) and other materials exhibiting the needed bending, expanding, contracting, and form changing properties. Two wires 1140 and 1142 to carry current to and from the electroactive polymer 1104 may be coated and placed along the pushwire 106 (shown in FIGS. 1A and 1B). Alternatively, the pushwire itself and/or internal strands of the pushwire may be used to replace one or both wires that would have been external to the core of the pushwire.

The electroactive sealing ring allows for sealing and unsealing to be achieved without translation of the microcatheter. In this way, a channel for delivering beneficial agents can be created more easily during postconditioning periods when the device is not occluding.

Methods of Using Electroactive Polymers to Enable Occlusion Using Flow Modulation Member

FIGS. 12A and 12B are a process flow chart for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIGS. 12A and 12B may be applied to assemblies with a single-lumen balloon catheter and a pushwire bearing a shape-changing sealing ring (such as an EAP sealing ring).

In step 1201, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 1202, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In optional step 1203, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter, but still proximal to the clot. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the larger catheter to a position distal to the location of the clot.

In step 1204, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. In step 1205, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a reperfusion member coupled to its distal end and an EAP sealing ring proximal to the reperfusion member. Some reperfusion members, such as those that may have clot-capture functionality, may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 1206, the active region will expand and engage with the clot. During all passes with a clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the reperfusion member contacts the clot.

A control handle (“voltage controller”), containing a voltage source (e.g., a battery) is affixed to the proximal end of the pushwire. By affixing the voltage controller, the electrical connectors from the voltage source join the wires 1140 and 1142 that develop voltage across the EAP as shown in FIGS. 11A-11D. A switch on the voltage controller is pressed, developing voltage across the EAP and causing the EAP to swell, thereby creating a seal between the pushwire and the microcatheter.

Following step 1206 in FIG. 12A the status of reperfusion should be assessed and the elapsed time tracked. Reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 1207 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with either (1) postconditioning 1210, if postconditioning has not been already performed on a prior pass; or (2) step 1211, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously.

In step 1206, if the blood vessel has not been sufficiently reperfused, then proceed to step 1207 where inflating fluid is pumped into the single-lumen microcatheter, thus inflating the flow modulation member and occluding the blood vessel. A determined period of wait-time “t” (e.g., 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 1208 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1209 with the insertion of a new guidewire. Steps 1204-1209 are repeated in subsequent passes until either (1) the predetermined maximum number of passes has been completed, in which case proceed with step 1213, or (2) the blood vessel is sufficiently reperfused, in which case proceed with either step 1210 if postconditioning has not been already performed or step 1211 if postconditioning was performed previously.

If the blood vessel is sufficiently reperfused after step 1206 or step 1207, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member (e.g., a balloon) is inflated and deflated in step 1210 according to a predetermined series of one or more postconditioning cycles. Voltage is maintained at least during the parts of the cycles where the balloon is inflated. The seal can simply be maintained throughout the postconditioning cycles. To administer beneficial agents through the microcatheter to the infarct region or clot, the seal can be temporarily removed by stopping voltage periodically during postconditioning, for example during the reperfusion periods within the cycles. Examples of postconditioning cycles are described in greater detail elsewhere herein.

According to some embodiments of the present invention, the balloon is inserted with, attached to, and flush with the external wall of the microcatheter. The balloon may be inflated and deflated either by manual or by automatic pumping of inflating fluid in and out of the microcatheter lumen, which is continuous with the balloon lumen via inflation holes. When inflating fluid is pumped through the microcatheter, it flows through the inflation holes in the catheter lumen wall and into the balloon. The balloon membrane expands against the blood vessel, blocking a substantial portion of the vessel's lumen. In a preferred embodiment, the balloon membrane contacts the inner lumen of the blood vessel to create a complete occlusion of blood flow. The balloon membrane is flexible so that it will conform to the blood vessel's wall. By having a blood flow-occluding balloon in place, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of inflating fluid from the microcatheter, the balloon also empties (i.e., deflates) and gradually resumes its former shape, once again becoming flush with the external wall of the microcatheter. Inflating fluid can be removed using suction or by relaxing the seal. With deflation, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 1211. In a given pass, after unsheathing the clot-capturing reperfusion member in step 1206 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the intermediate catheter (if present) and/or the larger catheter. Therefore, the intermediate and/or larger catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 1212, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 1212, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 1213. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1209 with the insertion of a new guidewire.

Intermediate Single-Lumen Balloon Catheters with Microcatheters Bearing Sealing Rings

The use of a movable seal disposed within a lumen that has a sealing region is certainly applicable beyond the pushwire/microcatheter context. In FIG. 13, for example, a rounded sealing ring 1304 is attached to a microcatheter 1302. The sealing region 1340 is on the inner lumen of an intermediate catheter 1308. The membrane for the balloon 1300 attaches to the intermediate catheter 1308 in the attachment regions 1330. When the rounded sealing ring 1304 is placed in the sealing region 1340 of the intermediate catheter, defined by a polymeric tube that may be made from the same material as the intermediate catheter 1308 (a different material may also be used) that creates a narrower lumen, inflating fluid 500 pushed through the lumen of the intermediate catheter 1308 will flow through the inflating holes 1322.

The embodiment shown in FIG. 13 is an assembly composed of a sealing ring 1304 mounted on a microcatheter 1302 and a single lumen intermediate catheter 1308, which provides enhanced navigability and allows for the delivery of the reperfusion member 108 (shown in FIGS. 1A and 1B, etc.) at the location of the clot. Clots tend to lodge in the Middle Cerebral Artery, where the vasculature is particularly tortuous. Using a sealing ring design eliminates the need for an additional lumen on the intermediate catheter and therefore increases flexibility.

The preferred length of the sealing ring is about 4 mm. However, different dimensions for the sealing ring may be used (e.g. from approximately 2 mm to approximately 10 mm in length). The diameter of the sealing ring is preferred to be the same as the inner diameter of the narrower region of the intermediate catheter. It is anticipated that matching diameters, e.g., about 0.046″, will provide adequate sealing while minimizing the risk of assembly jamming. However, different dimensions for the sealing ring may be used (e.g. from about 0.0350″ to 0.055″ in diameter).

The sealing ring can be attached to the microcatheter in many ways, (e.g., solvent bonding, gluing and interference fitting). In the preferred embodiment, the sealing ring is composed of the same material as that of the microcatheter; however, other materials may be used (e.g., silicone, PET, latex, nylon, and rubber).

The insert for the narrowing of the lumen can be attached to the intermediate catheter in many ways, for example: solvent bonding and interference fitting. In the preferred embodiment the sealing region insert 1340 in the lumen is composed of the same material as that of the microcatheter; however, other materials may be used. The intermediate catheter 1308 and the sealing region insert 1340 may be manufactured as one part. In this case, the intermediate catheter would be extruded at the desired diameter, for example a 4 French inner diameter. The narrower sealing region 1340 may be created by pinching or heat forming such that the both the inner and outer diameter of the intermediate catheter may be locally reduced simultaneously.

There are numerous ways that a sealing ring on the microcatheter can be used to create a seal that will permit the clot to pass through the intermediate catheter as well as facilitate postconditioning. The embodiments above are only examples.

The sealing ring allows for both the inflation fluid and microcatheter to use (or have) a single lumen. In the embodiment shown in FIG. 13, there is space 1306 between the microcatheter 1302 and the luminal wall of the intermediate catheter 1308 to allow the inflating fluid 500 (e.g., saline solution) to travel through and inflate the balloon 1300. Additionally, this space ensures reduced friction between the microcatheter 1302 and the intermediate catheter 1308, during the translation of one with respect to the other. The sealing ring may be positioned proximally to the portion of the microcatheter that will slide through the clot before deploying the reperfusion member (e.g. about 25 mm proximal to the distal tip of the microcatheter). The inner lumen of the intermediate catheter bears inflating holes 1322 (e.g., two holes in the embodiment shown) that connect the lumen of the balloon to the inner lumen 1306 of the intermediate catheter, to let the inflating fluid reach the cavity of the balloon. When translated into the narrower portion 1340 of the intermediate catheter 1308, the sealing ring 1304 creates a seal that prevents the inflating fluid 500 from flowing passed the sealing ring and freely out of the distal end of the intermediate catheter. Once the sealing ring 1304 is advanced into the narrower portion 1340 of the intermediate catheter 1308, pumping the inflation fluid 500 through the proximal end of the intermediate catheter will result in the inflation of the balloon 1300.

The sealing ring is preferred to be rounded to promote ease of entering the narrower portion of the intermediate catheter. By only contacting at one point, friction is minimized and the microcatheter can pass through the intermediate catheter without jamming. The sealing ring would only need to re-enter the intermediate catheter if the microcatheter is pushed too far away (e.g. beyond the distal end of the intermediate catheter).

The end of the intermediate catheter may be the same diameter as the non-sealing areas of the intermediate catheter, as is illustrated in this embodiment shown in FIG. 13. Having a wider lumen allows the clot to be drawn into the intermediate catheter (along with the reperfusion member) with less potential for resistance.

The preferred outer diameter shown of the microcatheter is about 2.3 French. However, microcatheter with diameters ranging from 1.5 French to 3 French may be used.

Intermediate Catheters Compatible with Microcatheters Bearing Sealing Rings

The inner diameter throughout the intermediate catheter may be the same as the diameter of the sealing ring; however, this is not the preferred embodiment.

The narrowed region may be about 4 mm long and its center located about 22 mm from the distal end of the intermediate catheter. The region of the microcatheter distal to the sealing ring 1304 has sufficient length so as to not let the sealing ring interfere with the clot when positioning the microcatheter adequately before positioning the reperfusion member adjacent to the clot.

Specifications follow for the preferred embodiment shown in FIG. 13. However a range of specifications may be used: The wall thickness of the intermediate catheter is about 100 ®m. In the wider part of the intermediate catheter, the gap 1306 between the outer diameter of the microcatheter and the inner diameter of the intermediate catheter—if the microcatheter is centered within the intermediate catheter—is about 283 μm. However, this gap may range from approximately 150 μm to 400 μm. The inner diameter of the wider portion of the intermediate catheter is 4 French. However, intermediate catheters having a range of diameters, for example 3 French to 5 French, may also be used.

This slightly wider intermediate catheter also allows for two ideal channels to deliver fluids to the infarcted tissue, in region of the clot and/or the clot itself. With both channels, medicine can reach this infarct area both during and in between clot retrieval passes. When the ring is not in the sealing region, both channels are available. Alternating applications of different medications may be used. One such fluid is contrast agent. Others include agents to treat reperfusion injury or help otherwise at the site of the clot. Tissue plasminogen activator (tPA) could also be applied locally—reducing the systemic risks of bleeding—and in lower overall quantities. Agents that may minimize reperfusion injury include cyclosporine, calpain inhibitors, sodium-calcium Na+/Ca2+ exchange inhibitors, monoclonal antibodies, temperature reducing agents, or agents that slow cell metabolism. Agents that may aid in removing a clot include tissue plasminogen activator and other agents that aid in dissolving, dislodging, or macerating clots. Agents that may otherwise benefit the patient's condition include, but are not limited to, pharmaceuticals or compounds commonly used for treating clots, preventing restenosis, intravascular device coatings such as vasodilators, nimodipine, sirolimus, or paclitaxel. The preferred embodiment will therefore provide an opportunity to use drugs that may help lessen the ischemic and reperfusion injuries and/or speed recovery.

The sealing ring may come in various shapes and dimensions. The sealing ring need not be shaped so as to resemble an ellipsoid with a hole through the center for the microcatheter. Indeed, it may be of numerous shapes.

Balloons Compatible with Microcatheters Bearing Sealing Rings

In this embodiment, the proximal end of the balloon would be located about 29 mm from the distal end of the intermediate catheter, such that it begins proximal to the location of the sealing holes and extends up to the distal end of the intermediate catheter. Note that the inflation holes should be proximal to the sealing region. In the embodiment shown the inflation holes are located about 26 mm from the distal end of the intermediate catheter. Positioning the inflation holes toward the proximal end of the balloon and having a longer balloon, allows the sealing region to be far enough away from the distal end of the intermediate catheter so that it does not interfere with the clot upon retrieval. A major advantage of having the balloon extend to the distal tip of the intermediate catheter is that the distance between the balloon and the reperfusion member should be short in order to minimize the chance of interference by a collateral artery during postconditioning. If another blood vessel were to intersect the occluded artery, between the clot and the balloon, then the balloon would not be able to cut off blood supply entirely during postconditioning. In other words the collateral blood vessel would not be blocked and continue supplying blood even when the balloon was fully inflated.

In all embodiments herein having a balloon, the membrane of the balloon may be constructed from various materials. Polypropylene is preferred but other materials may be used, including, but not limited to, thermoplastic polymers, elastomeric silicones, latexes, other polymers or a blend thereof. An example is ENGAGE™ polyolefin elastomers available from the Dow Chemical Company (Midland, Mich.). To reliably occlude while not damaging the artery, the balloon is soft, compliant and operated under a range of low pressures. The balloon may occlude the vessel at inflation pressures ranging from about 0.1 to 5 atm. The balloon is preferred to be one-size-fits-all-cerebral-vessels with balloon diameters ranging from about 1 to 5 mm in the inflated state. Alternatively, various intermediate may be manufactured with balloons of different sizes to accommodate a range of occluded vessel diameters. The target diameters of the different sized balloons may be 1 to 5 mm (i.e., different sizes for different diameter arteries). In an embodiment, the length of the balloon 1300 is preferred to be 30 mm (to allow a sufficient wide-diameter lumen at the distal tip of the intermediate catheter). However, a range of balloon lengths may be used (for example up to about 50 mm).

The balloon may be coated with various coatings, both to reduce friction between the balloon and the vessel and also to avoid adhesion of thrombus. For example, a hydrophilic coating such as polytetrafluoroethylene is preferred.

Radiopaque marker-bands 1324 (shown in FIG. 13) are preferred to be placed near the extremities of the balloon. It is preferred to place two marker-bands, one near the proximal end of the balloon and one near the distal end. In the preferred embodiment FIG. 13, the marker-bands are around the intermediate catheter, but within the inner lumen of the balloon. Alternatively, the marker-bands may be embedded within the plastic wall of the intermediate catheter. Radiopaque materials may also be incorporated within the material of the balloon membrane, or used to coat the balloon. The radiopaque materials will aid the operator in seeing the position, state of expansion, and rate of expansion of the balloon.

The inflating holes 1322 are cylindrical holes with a circular base and a diameter of about 150 μm. A range of diameters may also be used (e.g., from approximately 100 m to 400 μm). The inflating holes may be cut into the microcatheter or catheter using electron beam drilling, laser drilling, classical machining or other methods.

The balloon is attached to the microcatheter in the attachment regions 1330 on either side of the inflating membrane. The attachment regions may be contiguous bands around the intermediate catheter. The attachment regions keep the inflating solution from flowing out of the balloon. Many methods may be used to attach the balloon to the intermediate catheter (e.g., fusion bonding, ultrasonic welding, solvent bonding, induction welding, and dielectric welding).

Methods of Using Intermediate Single-Lumen Balloon Catheters with Microcatheters Bearing Sealing Rings

FIGS. 14A and 14B are a process flow chart for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIGS. 14A and 14B may be applied to assemblies with an intermediate single-lumen balloon catheter with a microcatheter bearing a sealing ring.

In step 1401, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 1402, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In step 1403, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. The intermediate catheter has a distal region in which its internal diameter locally decreases. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the larger catheter to a position distal to the location of the clot.

In step 1404, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. The microcatheter may but need not advance any further than the distal end of the guidewire. In step 1405, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a reperfusion member coupled to its distal end. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 1406, the active region will expand and engage with the clot. During all passes with the clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the sealing ring coupled to the microcatheter enters the narrow distal region of the intermediate catheter and creates a seal within the intermediate catheter lumen around the microcatheter, for retaining inflating fluid in the intermediate catheter (and balloon on the intermediate catheter).

Following step 1406, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 1407 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with either (1) postconditioning step 1410, if postconditioning has not been already performed on a prior pass; or (2) step 1411, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously. To deliver beneficial agents during postconditioning through the intermediate catheter, the seal can be temporarily removed by translating the intermediate catheter so that the sealing ring is no longer within the intermediate catheter's sealing region. Agents can be delivered through the large catheter or microcatheter without the need to remove a seal.

In step 1406, if the blood vessel has not been sufficiently reperfused, then proceed to step 1407 where inflating fluid is pumped into the intermediate catheter, thus inflating the flow modulation member and occluding the blood vessel. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 1408 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1409 with the insertion of a new guidewire. Steps 1404-1409 are repeated in subsequent passes until either (1) the predetermined maximum number of passes has been completed, in which case proceed with step 1413, or (2) the blood vessel is sufficiently reperfused, in which case proceed with either step 1410 if postconditioning has not been already performed or step 1411 if postconditioning was performed previously.

If the blood vessel is sufficiently reperfused after step 1406 or step 1407, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member (i.e., balloon) is inflated and deflated in step 1410 according to a determined series of one or more postconditioning cycles. Preferred examples of postconditioning cycles are described in greater detail elsewhere herein.

According to some embodiments of the present invention, the balloon is inserted with, attached to, and flush with the external wall of the microcatheter. The balloon may be inflated and deflated either by manual or by automatic pumping of inflating fluid in and out of the intermediate catheter lumen, which is continuous with the balloon lumen via inflation holes. When inflating fluid is pumped through the intermediate catheter, it flows through the inflation holes in the catheter lumen wall and into the balloon lumen. The balloon membrane expands against the blood vessel, blocking a substantial portion of the vessel's lumen. In a preferred embodiment, the balloon membrane contacts the inner lumen of the blood vessel to create a complete occlusion of blood flow. The balloon membrane is flexible so that it will conform to the blood vessel's wall. By having a blood-flow-occluding balloon in place, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of inflating fluid from the microcatheter, the balloon also empties (i.e., deflates) and gradually resumes its former shape, once again becoming flush with the external wall of the microcatheter. Inflating fluid can be removed using suction or by unsealing the intermediate catheter (via moving the sealing region away from the sealing ring). With deflation, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 1411. In a given pass, after unsheathing the clot-capturing reperfusion member in step 1406 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the intermediate catheter and the larger catheter. Therefore, the intermediate catheter and large catheter remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 1412, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter or intermediate catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 1412, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 1413. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1409 with the insertion of a new guidewire.

Intermediate Single-Lumen Balloon Catheters with Electroactive Sealing Members

Another example of using an electroactive polymer (EAP) in an enabling step for the flow modulation member is for creating a seal for inflating fluid. Such seals can be between various elements. One such embodiment that will be discussed below is between a microcatheter and an intermediate catheter. The intermediate single-lumen balloon catheters compatible with microcatheters bearing sealing rings rely on translation to effect a complete seal. In contrast, electricity can be used instead of movement to create the seal. Use of EAPs, for example, is one way to use electricity to control sealing FIGS. 15A-15B.

In the illustrated example of an embodiment, an electroactive ring 1504 constricts (as illustrated in FIG. 15A) when voltage is developed across the material and it is “activated.” When constricting, the EAP pulls the membrane 1544 inward. The membrane contacts the microcatheter 1502, creating a seal. With the seal in place, inflating solution 500 can be pumped into the lumen 1506 of the intermediate catheter, inflating the balloon (starting about 2 mm 1546 proximal to the distal end of the intermediate catheter and spanning about 11 mm 1548) on the intermediate catheter and causing occlusion of the vessel. The balloon (which can be similar in configuration and dimensions as previously described) is attached to the catheter at 1530, forming a fluid tight seal between the catheter and the balloon along the circumference of the catheter. In the illustrated embodiment, the balloon is attached at a proximal end and a distal end of the balloon membrane.

The embodiment of the intermediate catheter depicted has a flexible distal segment 1544 starting at about 3 mm proximal to the distal end of the intermediate catheter and spanning 7 mm 1550 in length. This segment is thinner or is made of material that is more flexible than that of the majority of the intermediate catheter 1508. In the illustrated embodiment the EAP ring 1504 is about 3 mm long (i.e., 1544 in the illustration) and is placed centrally on the outside of the more flexible catheter wall segment 1544. The EAP ring constricts as illustrated in FIG. 15A when voltage is developed across. When electric current is applied, the EAP ring 1504 brings the flexible intermediate catheter segment into contact with the outer surface of the microcatheter, creating a seal and allowing the balloon on the intermediate catheter to inflate. When external voltage ceases, the EAP ring relaxes, and the inner diameter of the flexible region returns to its resting dimensions, thereby not interfering with removal of the reperfusion member and any potential thrombus.

The EAP band shown in FIGS. 15A and 15B is about 100 μm in height so that it does not interfere with navigability and does not significantly increase the overall diameter of the intermediate catheter.

The inner diameter of the EAP will contract from approximately the inner diameter of the intermediate catheter (3.1 French if a 4 French catheter is used) to the outer diameter of the microcatheter (for example 2.1 French).

Small wires 1540 and 1542 (illustrated in FIGS. 15A, 15B) are embedded in the intermediate catheter or run along the outside of the intermediate catheter to carry voltage to and from the EAP. The electrically controlled seal may be made of various materials with suitable constricting, bending or swelling properties. For example the EAP may include PPy (Polypyrrole), NAFION®, and ionic polymer-metal composites (ionic EAPs). Other numbers designate similar elements described in previous embodiments with a prefix 15 (e.g. the radiopaque markers introduced in FIGS. 1A and 11B as 124 are indicated by 1524.

Methods of Using Intermediate Single-Lumen Balloon Catheters with Electroactive Sealing Members

FIGS. 16A and 16B are process flow charts for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIGS. 16A and 16B may be applied to assemblies with a single-lumen intermediate balloon catheter and a microcatheter bearing an expandable EAP sealing ring.

In step 1601, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 1602, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In step 1603, an intermediate single-lumen balloon catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. In the event of subsequent passes, the intermediate single-lumen balloon catheter saves time in navigating a new guidewire from the distal end of the larger catheter to a position distal to the location of the clot.

In step 1604, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. In step 1605, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a reperfusion member coupled to its distal end and an EAP sealing ring proximal to the reperfusion member. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 1606, the active region will expand and engage with the clot. During all passes with a clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the reperfusion member contacts the clot. A control handle (“voltage controller”), containing a voltage source such as a battery, is affixed to the proximal end of the pushwire. By affixing the voltage controller, the electrical connectors from the voltage source join the wires 1540 and 1542 that develop voltage across the EAP. A switch on the voltage controller is pressed, developing voltage across the EAP and causing the EAP to swell, thereby creating a seal between the microcatheter and the intermediate catheter.

Following step 1606, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 1607 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with either (1) postconditioning 1610, if postconditioning has not been already performed on a prior pass, or (2) step 1611, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously. To administer beneficial agents through the intermediate catheter to the infarct region or clot, the seal can be temporarily removed by stopping voltage periodically during postconditioning, for example during the reperfusion periods within the cycles. Examples of postconditioning cycles are described in greater detail elsewhere herein. Agents can be delivered through the large catheter and microcatheter without the need to remove a seal.

In step 1606, if the blood vessel has not been sufficiently reperfused, then proceed to step 1607 where inflating fluid is pumped into the intermediate catheter lumen, thus inflating the flow modulation member and occluding the blood vessel. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 1608 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1609 with the insertion of a new guidewire. Steps 1604-1609 are repeated in subsequent passes until either (1) the predetermined maximum number of passes has been completed, in which case proceed with step 1613, or (2) the blood vessel is sufficiently reperfused, in which case proceed with either step 1610 if postconditioning has not been already performed or step 1611 if postconditioning was performed previously.

If the blood vessel is sufficiently reperfused after step 1606 or step 1607, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member (i.e., a balloon) is inflated and deflated in step 1610 according to a determined series of one or more postconditioning cycles. Voltage is maintained at least during the parts of the cycles where the balloon is inflated. The seal can simply be maintained throughout the postconditioning cycles. To administer beneficial agents through the microcatheter to the infarct region or clot, the seal can temporarily be removed by stopping voltage periodically during postconditioning, for example during the reperfusion periods within the cycles. Examples of postconditioning cycles are described in greater detail elsewhere herein.

According to some embodiments of the present invention, the balloon is inserted with, attached to, and flush with the external wall of the microcatheter. The balloon may be inflated and deflated either by manual or by automatic pumping of inflating fluid in and out of the intermediate catheter lumen, which is continuous with the balloon lumen via inflation holes. When inflating fluid is pumped through the intermediate catheter, it flows through the inflation holes in the catheter lumen wall and into the balloon. The balloon membrane expands against the blood vessel, blocking a substantial portion of the vessel's lumen. In a preferred embodiment, the balloon membrane contacts the inner lumen of the blood vessel to create a complete occlusion of blood flow. The balloon membrane is flexible so that it will conform to the blood vessel's walls. By having a blood flow-occluding balloon in place, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of inflating fluid from the microcatheter, the balloon also empties (i.e., deflates) and gradually resumes its former shape, once again becoming flush with the external wall of the intermediate catheter. Inflating fluid can be removed using suction or by relaxing the seal. With deflation, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 1611. In a given pass, after unsheathing the clot-capturing reperfusion member in step 1606 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the intermediate catheter and larger catheter. Therefore, the intermediate and large catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the large catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 1612, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 1612, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 1613. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1609 with the insertion of a new guidewire.

Other Single-Lumen Balloon Catheter Embodiments of a Flow Modulation Member with Passive Sealing Mechanisms

Alternatively, the lumen of the microcatheter may be tapered at its distal tip such that the distal tip creates a seal against the pushwire (herein referred to as a “sealing tip”). FIG. 17 illustrates a microcatheter with a sealing tip according to some embodiments of the present invention. The sealing tip 1700 may be constructed from an elastic material that can expand to accommodate the compressed clot-capturing reperfusion member but then contract (facilitated by bending in region 1704), after the clot-capturing reperfusion member passes through, to create a seal where the region of the flexible tip 1702 contacts the pushwire and allow for inflation of the balloon. The tip widens when pushed by the reperfusion member. An example of such material is silicon rubber. The embodiment shown in FIG. 17 is but one example. In FIG. 17, the flexible tip 1700 is a single part that goes over and attaches, in region 1706, to the microcatheter. The tip is secured around the distal end of the microcatheter. FIG. 17 features a tip that extends beyond the distal edge of the microcatheter. The same reference numerals are used for elements described in earlier embodiments.

There are various ways to build a flexible tipped microcatheter. Two such embodiments are illustrated in FIGS. 17-18. FIG. 18 creates a flexible sealing region by having a spongy material 1800 inside of tip of the microcatheter. One example of a class of materials that may be used is shape memory polyurethanes. The spongy material compresses against the microcatheter walls to allow the reperfusion member to pass through and then hugs the microcatheter to create a seal. The same reference numerals are used for elements described in earlier embodiments.

In flexible tipped embodiments, it is preferred to have a clot-capturing reperfusion member that is closed at its distal end, in order to present a streamlined insertion profile to the sealing tip.

Methods of Using Other Single-Lumen Balloon Catheter Embodiments of a Flow Modulation Member with Passive Sealing Mechanisms

FIGS. 19A and 19B are process flow charts for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIGS. 19A and 19B may be applied to assemblies with single-lumen balloon catheter embodiments of a flow modulation member that employs sealing mechanisms that are passive in their method of operation.

In step 1901, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 1902, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In optional step 1903, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the large catheter to a position distal to the location of the clot.

In step 1904, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. In step 1905, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a reperfusion member coupled to its distal end. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 1906, the active region will expand and engage with the clot. During all passes with a clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the reperfusion member contacts the clot.

Following step 1906, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 1907 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with either (1) postconditioning 1910, if postconditioning has not been already performed on a prior pass; or (2) step 1911, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously. Beneficial agents may be delivered during postconditioning or other times through lumens that are not sealed.

In step 1906, if the blood vessel has not been sufficiently reperfused, then proceed to step 1907 where inflating fluid is pumped into the single-lumen microcatheter, thus inflating the flow modulation member and occluding the blood vessel. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 1908 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1909 with the insertion of a new guidewire. Steps 1904-1909 are repeated in subsequent passes until either (1) the blood vessel is sufficiently reperfused, in which case proceed with either step 1910 if postconditioning has not been already performed or step 1911 if postconditioning was performed previously, or (2) the predetermined maximum number of passes has been completed, in which case proceed with step 1913.

If the blood vessel is sufficiently reperfused after step 1906 or step 1907, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member (i.e., a balloon) is inflated and deflated in step 1910 according to a determined series of one or more postconditioning cycles. The flow modulation member can be inflated without the operator performing additional functions to create a seal. Examples of postconditioning cycles are described in greater detail elsewhere herein.

According to some embodiments of the present invention, the balloon is inserted with, attached to, and flush with the external wall of the microcatheter. The balloon may be inflated and deflated either by manual or by automatic pumping of inflating fluid in and out of the microcatheter lumen, which is continuous with the balloon lumen via inflation holes. When inflating fluid is pumped through the microcatheter, it flows through the inflation holes in the catheter lumen wall and into the balloon. The balloon membrane expands against the blood vessel, blocking a substantial portion of the vessel's lumen. In a preferred embodiment, the balloon membrane contacts the inner lumen of the blood vessel to create a complete occlusion of blood flow. The balloon membrane is flexible so that it will conform to the blood vessel's walls. By having a blood flow-occluding balloon in place, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of inflating fluid from the microcatheter, the balloon also empties (i.e., deflates) and gradually resumes its former shape, once again becoming flush with the external wall of the microcatheter. Inflating fluid can be removed by suction. With deflation, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 1911. In a given pass, after unsheathing the clot-capturing reperfusion member in step 1906 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the intermediate catheter (if present) and/or the larger catheter. Therefore, the intermediate and/or larger catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 1912, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 1912, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 1913. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 1909 with the insertion of a new guidewire.

Multiple-Lumen Balloon Embodiments of a Flow Modulation Member Double-Lumen Balloon Microcatheters

As illustrated in FIGS. 20A and 20B, a double lumen balloon microcatheter may be used in lieu of the single-lumen balloon microcatheter previously described. In this case, the profile of the inner lumen 2000 will be constant i.e. constant inner diameter. Here, the inflating solution 500 would have its own dedicated lumen 2006 within the walls 2008 and 2010 of the microcatheter. The inflating solution would not come into contact with the pushwire 106 or reperfusion member 108. Radiopaque markers 2024 delineate the extremities of the balloon, as illustrated in FIG. 20B.

In the preferred embodiment for a double lumen balloon microcatheter FIGS. 20A, 20B, there are separate coaxial lumens 20C, 20D and 20E. The lumen for the inflating solution 2006 (“inflating lumen”) in the embodiment shown is narrower than the lumen 2000 for the pushwire. In the embodiment depicted in FIGS. 20A, 20B, the diameter of the inner lumen is about 0.018″, the inner wall 2008 and outer wall 2010 are about 85 μm thick, and the gap between the two walls is about 50 μm. These dimensions are examples and may vary.

The outer diameter of the outer wall 2010 is preferred to be about 0.035″ but may vary from about 0.021″ to 0.050″. Inflating holes 2002 in the outer wall 2010 of the microcatheter connect the lumen used for the inflating solution 500 to the balloon 2004. Rigidity in the longitudinal direction is important to avoid wrinkling (a unequal longitudinal translation between the two lumens, which may create a wavy surface). Therefore, there is a connection 2012 between the two lumens in FIG. 20D. In other embodiments, the two lumens are largely free-floating FIG. 20C. They may be connected at the proximal and distal ends and/or connected intermittently (e.g. having a connection 2012 of length about 2 mm repeatedly positioned once every about 5 cm).

The intermittent connections serve to prevent wrinkling while minimizing rigidity. The intermittent connections need not be arranged in a parallel line with respect to the central axis. To have even rigidity in all directions the intermittent connections may be distributed in various patterns (e.g. random, helical, every 120 degrees etc.). The intermittent connections may be created by first manufacturing two separate tubes and then using induction welding to attach the outer tube to the inner tube at various points. In this case, the outer tube may be slightly deformed (e.g. pushed inward) at the locations where induction welding has been used. In other embodiments, there are three or more separate lumens as illustrated in FIG. 20E. The preferred method for manufacturing the double lumen balloon catheter is extrusion.

The method of inflation of the balloon on a double lumen catheter, manually or by pump, is more straightforward than in the single lumen-sealing ring embodiment. A pressure transducer is connected to one of the ports connected to the proximal end of the inflating lumen. Saline solution—or another inflating fluid, which may contain contrast agent—is pushed through the inflating lumen. As a consequence, the pressure of the inflating fluid increases, inflating fluid goes through the inflating holes, and the balloon inflates. No locking is required, as with the ring design, to enable inflation. The method for operation and postconditioning is similar to that for the other balloons described, such as the single-lumen balloon with a sealing ring, except there is no sealing ring and therefore a step to lock the sealing ring would not be needed.

Methods of Using Double-Lumen Balloon Microcatheters

FIGS. 21A and 21B are a process flow chart for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIGS. 21A and 21B may be applied to assemblies with double-lumen balloon microcatheter embodiments of a flow modulation member.

In step 2101, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 2102, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In optional step 2103, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the large catheter to a position distal to the location of the clot.

In step 2104, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. In step 2105, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a reperfusion member coupled to its distal end. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 2106, the active region will expand and engage with the clot. During all passes with a clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the reperfusion member contacts the clot.

Following step 2106, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 2107 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with either (1) postconditioning 2110, if postconditioning has not been already performed on a prior pass; or (2) step 2111, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously. Beneficial agents may be delivered during postconditioning or other times through lumens that lead to the artery.

In step 2106, if the blood vessel has not been sufficiently reperfused, then proceed to step 2107 where inflating fluid is pumped into the inflation lumen of the double-lumen microcatheter, thus inflating the flow modulation member and occluding the blood vessel. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 2108 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 2109 with the insertion of a new guidewire. Steps 2104-2109 are repeated in subsequent passes until either (1) the blood vessel is sufficiently reperfused, in which case proceed with either step 2110 if postconditioning has not been already performed or step 2111 if postconditioning was performed previously, or (2) the predetermined maximum number of passes has been completed, in which case proceed with step 2113.

If the blood vessel is sufficiently reperfused after step 2106 or step 2107, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member (i.e., a balloon) is inflated and deflated in step 2110 according to a determined series of one or more postconditioning cycles. In contrast to some other embodiments, the flow modulation member can be inflated without the operator performing additional functions to create a seal. Examples of postconditioning cycles are described in greater detail elsewhere herein.

According to some embodiments of the present invention, the balloon is inserted with, attached to, and flush with the external wall of the microcatheter. The balloon may be inflated and deflated either by manual or by automatic pumping of inflating fluid in and out of the inflation lumen of the microcatheter, which is continuous with the balloon lumen via inflation holes. When inflating fluid is pumped through the inflation lumen of the microcatheter, it flows through the inflation holes and into the balloon. The balloon membrane expands against the blood vessel, blocking a substantial portion of the vessel's lumen. In a preferred embodiment, the balloon membrane contacts the inner lumen of the blood vessel to create a complete occlusion of blood flow. The balloon membrane is flexible so that it will conform to the blood vessel's walls. By having a blood flow-occluding balloon in place, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of inflating fluid from the microcatheter, the balloon also empties (i.e., deflates) and gradually resumes its former shape, once again becoming flush with the external wall of the microcatheter. Inflating fluid can be removed by suction. With deflation, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 2111. In a given pass, after unsheathing the clot-capturing reperfusion member in step 2106 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the intermediate catheter (if present) and/or the larger catheter. Therefore, the intermediate and/or larger catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 2112, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 2112, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 2113. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 2109 with the insertion of a new guidewire.

Intermediate Double-Lumen Balloon Catheters

FIGS. 22A and 22B illustrate an additional way of using a balloon for postconditioning is to use an additional catheter 2202 disposed between the microcatheter 102 and the large catheter (e.g. size 6 French guide catheter) 2204. This additional catheter 2202 may be a double lumen balloon catheter (herein referred to as “intermediate double lumen catheter”), and may be of size 5 French. The intermediate double lumen catheter may be any number of sizes, but is likely to range from 3 French to 5.5 French. The intermediate double lumen catheter depicted in FIGS. 22A and 22B bears balloon 2200. The balloon is attached to the intermediate catheter in the attachment region 2230 on either side of the inflating membrane and is delineated by radiopaque markers 2224. However, intermediate single lumen catheters, which may or may not have a balloon, may also be used. Flexibility is an important characteristic for this intermediate double lumen catheter, to allow it to pass through the torturous curves of cerebral vessels. Reperfusion would be performed in cycles by using an inflating solution. It would be controlled by a syringe or pump, similarly to the balloon described in other sections of this document.

The large catheter 2204 is able to advance up to the internal carotid artery at the distal portion of the neck. The intermediate double lumen catheter 2202 would enter smaller tortuous arteries, such as the MCA, to conduct postconditioning as close to the location of the clot as possible, using a balloon 2200 near the distal end of the intermediate catheter.

The microcatheter 102 would be within the intermediate double lumen catheter 2202 and deploy the pushwire 106 and reperfusion member 108. The profile of the inner lumen 2206 will be constant i.e. constant inner diameter. Here, the inflating solution 500 would have its own dedicated lumen 2208 within the walls 2210 and 2212 of the intermediate double lumen catheter. The inflating solution would not come into contact with the pushwire 106 or reperfusion member 108.

In a preferred embodiment for an intermediate double lumen catheter FIGS. 22A-22B, there are separate coaxial lumens (similar to FIG. 20C). The lumen for the inflating solution 2208 (herein referred to as “inflating lumen”) in the embodiment shown is narrower than the lumen for the microcatheter 2206. Connectors 2012 (described in more detail with respect to FIGS. 20C and 20E) may attach the walls of the two lumens. In the embodiment depicted in FIG. 22A, 22B the diameter of the inner lumen 2206 is 0.026″, the inner wall 2210 and outer wall 2212 are 100 μm thick, and the gap between the two walls is 100 μm. These dimensions are examples and may vary.

The outer diameter of the outer wall 2212 is preferred to be about 0.050″ but may vary, for example, from about 0.040″ to 0.070″. Inflating holes 2222 through the outer wall 2212 of the intermediate double lumen catheter connect the lumen used for the inflating solution 500 to the balloon 2200.

Methods of Using Intermediate Double-Lumen Balloon Catheters

FIGS. 23A and 23B are process flow charts for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIGS. 23A and 23B may be applied to assemblies with double-lumen balloon intermediate catheter embodiments of a flow modulation member.

In step 2301, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 2302, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In step 2303, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the large catheter to a position distal to the location of the clot.

In step 2304, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. In step 2305, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a reperfusion member coupled to its distal end. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 2306, the active region will expand and engage with the clot. During all passes with a clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the reperfusion member contacts the clot.

Following step 2306, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 2307 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with either (1) postconditioning 2310, if postconditioning has not been already performed on a prior pass; or (2) step 2311, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously.

Postconditioning cycles are performed by inflating and deflating the balloon (via the dedicated lumen of the intermediate catheter) to occlude and reperfused the artery, respectively. The inflation/deflation may be performed manually (e.g. with a syringe) and automatically (e.g. with a pump and computerized control system). Beneficial agents may be delivered during postconditioning or other times through lumens that lead to the artery.

In step 2306, if the blood vessel has not been sufficiently reperfused, then proceed to step 2307 where inflating fluid is pumped into the inflating lumen of the intermediate double-lumen catheter, thus inflating the flow modulation member and occluding the blood vessel. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 2308 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 2309 with the insertion of a new guidewire. Steps 2304-2309 are repeated in subsequent passes until either (1) the blood vessel is sufficiently reperfused, in which case proceed with either step 2310 if postconditioning has not been already performed or step 2311 if postconditioning performed previously, or (2) the predetermined maximum number of passes has been completed, in which case proceed with step 2313.

If the blood vessel is sufficiently reperfused after step 2306 or step 2307, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member (i.e., a balloon) is inflated and deflated in step 2310 according to a determined series of one or more postconditioning cycles. In contrast to some other embodiments, the flow modulation member can be inflated without the operator performing additional functions to create a seal. Examples of postconditioning cycles are described in greater detail elsewhere herein.

According to some embodiments of the present invention, the balloon is inserted with, attached to, and flush with the external wall of the microcatheter. The balloon may be inflated and deflated either by manual or by automatic pumping of inflating fluid in and out of the inflation lumen of the double-lumen intermediate catheter, which is continuous with the balloon lumen via inflation holes. When inflating fluid is pumped through the inflation lumen of the double-lumen intermediate catheter, it flows through the inflation holes into the balloon. The balloon membrane expands against the blood vessel, blocking a substantial portion of the vessel's lumen. In a preferred embodiment, the balloon membrane contacts the inner lumen of the blood vessel to create a complete occlusion of blood flow. The balloon membrane is flexible so that it will conform to the blood vessel's walls. By having a blood flow-occluding balloon in place, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of inflating fluid from the inflation lumen of the double-lumen intermediate catheter, the balloon also empties (i.e., deflates) and gradually resumes its former shape, once again becoming flush with the external wall of the microcatheter. Inflating fluid can be removed using suction. With deflation, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 2311. In a given pass, after unsheathing the clot-capturing reperfusion member in step 2306 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the double-lumen intermediate catheter and the larger catheter. Therefore, the double-lumen intermediate catheter and/or larger catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or double-lumen intermediate catheter to limit the dispersion of secondary emboli.

In step 2312, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 2312, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 2313. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 2309 with the insertion of a new guidewire.

Other Multiple-Lumen Balloon Catheter Embodiments of a Flow Modulation Member

In some balloon flow modulation systems, a conduit for balloon-inflating fluid (e.g. a saline solution) or gas is attached to the expandable balloon, and may be threaded through or alongside the microcatheter or incorporated into the walls of the microcatheter itself. According to some embodiments, a thinner and more flexible tube for the inflating-fluid runs along the outside of the microcatheter. The tube may run alongside the microcatheter according to a helical, straight, or other pattern, and the tube may either be unattached or attached (loosely, strongly, or just at points) to the microcatheter. FIG. 24 illustrates a balloon 2400 fed by an inflating-fluid tube 2404, which is wrapped around the outside of a microcatheter 2402 in a helical pattern.

According to some embodiments, a conduit for the inflating-fluid is created as a hollow space within the walls of the microcatheter. The conduit may run inside the microcatheter walls according to a helical, straight, or other pattern. In preferred embodiments, a helical pattern—winding around the central longitudinal axis (identified in some illustrations by reference numeral 902) of the microcatheter—is used for the conduit or any aspects that add to microcatheter rigidity (e.g., posts). FIG. 25 illustrates a microcatheter with a hollow space 2506 between its outer walls 2504 and its inner walls 2502, held open for the passage of inflating fluid by posts 2510. Posts may be of different widths. In certain embodiments, the posts are so wide that they connect to each other, and one continuous tubular or rectangular conduit winds between the inner and outer walls of the microcatheter in a helical pattern.

According to some embodiments, a separate microcatheter may carry the inflating fluid through its central lumen (without a guidewire inside). In these embodiments, the flow modulation balloon may be located anywhere in the blood vessel and may not be attached to the same microcatheter and guidewire that deliver a reperfusion member.

The flow modulation member may be positioned in various locations relative to the microcatheter, guidewire, clot, and reperfusion member. According to some embodiments, a balloon may be deployed (i.e., inflated) from or attached to a point proximal to the distal end of the microcatheter, the distal end of the microcatheter, on the guidewire proximal to the reperfusion member, the distal end of the reperfusion member, or the distal end of the guidewire. Unlike other embodiments of the flow modulation member, a balloon does not need to be re-sheathed, just deflated. Because the distal end of the microcatheter is not needed for re-sheathing, the flow modulation balloon may be deployed either proximally or distally to the clot. If the balloon is positioned on an extension of the reperfusion member or the guidewire, distal to the clot, the balloon could also prevent the clot or emboli from being left behind or traveling to another vascular site when a reperfusion member is pulled out of the body.

Methods of Using Other Multiple-Lumen Balloon Catheter Embodiments of a Flow Modulation Member

FIGS. 26A and 26B are process flow charts for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIGS. 26A and 26B may be applied to assemblies with other multiple-lumen balloon catheter embodiments of a flow modulation member.

In step 2601, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 2602, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In optional step 2603, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the large catheter to a position distal to the location of the clot.

In step 2604, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. In step 2605, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a reperfusion member coupled to its distal end. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 2606, the active region will expand and engage with the clot. During all passes with a clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the reperfusion member contacts the clot.

Following step 2606, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 2607 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with either (1) postconditioning 2610, if postconditioning has not been already performed on a prior pass; or (2) step 2611, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously. Postconditioning cycles are performed by inflating and deflating the balloon (via the inflation lumen of the catheter) to occlude and reperfused the artery, respectively. The inflation/deflation may be performed manually (e.g. with a syringe) and automatically (e.g. with a pump and computerized control system). Beneficial agents may be delivered during postconditioning or other times through lumens that lead to the artery.

In step 2606, if the blood vessel has not been sufficiently reperfused, then proceed to step 2607 where inflating fluid is pumped into the single microcatheter lumen, thus inflating the flow modulation member and occluding the blood vessel. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 2608 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 2609 with the insertion of a new guidewire. Steps 2604-2609 are repeated in subsequent passes until either (1) the blood vessel is sufficiently reperfused, in which case proceed with either step 2610 if postconditioning has not been already performed or step 2611 if postconditioning performed previously, or (2) the predetermined maximum number of passes has been completed, in which case proceed with step 2613.

If the blood vessel is sufficiently reperfused after step 2606 or step 2607, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member (i.e., a balloon) is inflated and deflated in step 2610 according to a determined series of one or more postconditioning cycles. In contrast to some other embodiments, the flow modulation member can be inflated without the operator performing additional functions to create a seal. Examples of postconditioning cycles are described in greater detail elsewhere herein.

According to some embodiments of the present invention, the balloon is inserted with, attached to, and flush with the external wall of the catheter. The balloon may be inflated and deflated either by manual or by automatic pumping of inflating fluid in and out of the inflation lumen of the catheter, which is continuous with the balloon lumen via inflation holes. When inflating fluid is pumped through the inflation lumen of the catheter, it flows through the inflation holes and into the balloon. The balloon membrane expands against the blood vessel, blocking a substantial portion of the vessel's lumen. In a preferred embodiment, the balloon membrane contacts the inner lumen of the blood vessel to create a complete occlusion of blood flow. The balloon membrane is flexible so that it will conform to the blood vessel's walls. By having a blood flow-occluding balloon in place, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of inflating fluid from the inflation lumen of the catheter, the balloon empties (i.e., deflates) and gradually resumes its former shape, once again becoming flush with the external wall of the catheter. Inflating fluid can be removed using suction. With deflation, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter (whether it has single or multiple lumina) and pushwire are removed from the body in step 2611. In a given pass, after unsheathing the clot-capturing reperfusion member in step 2606 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the intermediate catheter (if present) and/or the larger catheter. Therefore, the intermediate and/or larger catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 2612, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 2612, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 2613. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 2609 with the insertion of a new guidewire.

Catheter-Constrained Embodiments of a Flow Modulation Member

The flow modulation member may be self-expanding and attached to the pushwire proximal to the reperfusion member. In these embodiments, the flow modulation member is deployed by translating the microcatheter so as to unsheathe the flow modulation member. To create cycles, flow is restored by resheathing the flow modulation member with the microcatheter.

According to some embodiments, the flow modulation member features an umbrella-like shape. FIGS. 27A-27C illustrates an embodiment of an umbrella-like flow modulation member 2700 in a fully expanded state with views from three different angles. The microcatheter 2706 has been translated proximally along the pushwire 2708 to release the flow modulation member 2700. The proximal portion of the flow modulation member 2700 exits the distal end of the microcatheter 2706 while the distal portion of the flow modulation member 2700 contacts the luminal walls 114 of the blood vessel to occlude blood flow from the proximal direction 116. The flow modulation member 2700 has struts 2704 to support a blood-flow-occluding membrane 2702. A simplified version of a reperfusion member 108 is attached to the pushwire 2708 distal to the flow modulation member 2700 at joint 110.

In the embodiment shown in FIGS. 27A-27C, the flow modulation member 2700 is designed with a strut length of about 1.4 mm for blood vessels with a radius of 1 mm, and is positioned with the location of its proximal strut ends about 10 mm proximal to the base of the reperfusion member. Generally, the distance between the location of a flow modulation member's proximal strut ends and the base of a reperfusion member may range anywhere from several centimeters to none (e.g., overlapping).

Frames and Struts

In accordance with certain embodiments, one or more struts form the frame of the flow modulation member. In an umbrella-like flow modulation member, struts generally exert a force to expand latitudinally and may spread the occlusion membrane across the blood vessel aperture. Structures, geometries, patterns, and numbers of struts in a flow modulation member may be varied to achieve a desired force of expansion, flexibility, and ease of re-sheathing. To optimize the opening and closing trajectory, force against the blood vessel wall, resistance against blood flow, and degree of occlusion, the flow modulation member may have a different number of primary struts, secondary struts, and non-linear geometries. FIG. 28 illustrates an embodiment of an umbrella-like flow modulation member expanded latitudinally from the central longitudinal axis 902 with an occlusion membrane 2802 supported by a lattice pattern of struts 2800. While the lattice has advantages, if the density of lattice pattern of struts 2800 is too high the ease of re-sheathing the flow modulation member may be hindered.

According to a preferred embodiment, FIGS. 29 and 30 illustrate two views of an umbrella-like flow modulation member 2906 with six primary longitudinal struts 2908. Although six primary struts are preferred, a smaller or larger number of primary struts may be used. In FIG. 29, the primary struts 2908 span the substantial length of the flow modulation member 2906, attaching at their proximal ends to a pushwire 2912 at connection 2904 to ring 2902, and running parallel to a plane of the central longitudinal axis 902 while expanding latitudinally. However, the edge 2900 of an occlusion membrane may extend past the distal ends of the primary struts 2908. As shown in FIGS. 29 and 30, the outer circle (shown in dotted lines in FIG. 29) is the distal edge of the occlusion membrane 2900.

In accordance with some embodiments, the form and curvature of the self-expanding primary struts must be sufficient to reach the targeted blood vessel wall with sufficient spring force to block blood flow when unsheathed from the microcatheter. FIGS. 31A-31D illustrate four exemplary embodiments of primary strut curvature when the strut is in its natural expanded state from a view parallel to the central longitudinal axis. For each embodiment, a strut 2908 is shown between the central longitudinal axis 902 where it connects to pushwire 2708 and contacts the blood vessel wall 114 (also shown in previous illustrations).

In the preferred embodiment of FIG. 31A, a first section 3100 of the strut 2908(a) curves with increasing slope away from the central axis 902, convex to the flow of blood. A second section 3102 of the strut 2908(a) is substantially straight and extends from the first curved section 3100. A third section 3104 of the strut 2908(a) continues from the second section 3102, concave to the flow of blood with decreasing slope relative to the central axis 902. A fourth section 3106 of the strut 2908(a) is substantially parallel to the central axis 902 and extends the third section 3104 until the strut is flush with the blood vessel wall 114. The fourth section 3106 increases the area of contact between the strut and the blood vessel wall, which further stabilizes the flow modulation member, thus strengthening its blood-flow-blocking capabilities by increasing the amount of force it can apply without damaging the blood vessel and surrounding brain tissue. Thus, the fourth section 3106 may allow an operator to perform postconditioning with greater speed and effectiveness.

Another advantage of the primary strut curvature shown in FIG. 31A is that the small slope of the first section 3100 (relative to the central longitudinal axis 902) provides finer control of the aperture of the flow modulation member because movement of the umbrella-like flow modulation member in and out of the microcatheter along the first section 3100 of the struts translates into a smaller difference in the area of the luminal latitudinal plane blocked by the member than if the same movement is made along the second section 3102.

Other primary strut curvatures are contemplated. Generally, a convex umbrella surface is more stable than a concave umbrella surface because blood flow pushing against a concave configuration has a greater propensity to collapse the umbrella. Embodiments of a flow modulation member with convex umbrella surfaces tend to exert more radial force against the blood vessel wall as blood flows against them, therefore creating a tighter seal. For example, FIG. 31B illustrates a strut 2908(b) with one curved section of continuously increasing slope away from the central axis 902, convex to the flow of blood for greater stability. Meanwhile, FIG. 31C illustrates a strut 2908(c) with one curved section of continuously decreasing slope away from the central axis 902, concave to the flow of blood, useful perhaps for milder occlusions or other clinical indications. FIG. 31D illustrates a strut 2908(d) with two curved sections, the proximal section continuously increasing in slope and convex to the flow of blood, the second distal section continuously decreasing in slope and concave to the flow of blood.

In accordance with most embodiments, the potential radius of an umbrella-like flow modulation member at its distal end, should be substantially similar to, or greater than, the radius of the targeted blood vessel. When fully deployed, the distal end of the flow modulation member is compressed by the blood vessel walls. This compression allows the flow modulation member to exert an outward radial force on the vessel walls. Thus, different sizes of flow modulation members are necessary to achieve the desired outward radial force for different sizes of blood vessels. For example, the flow modulation member's distal radius may range from 1 mm to 4 mm in its deployed state.

FIGS. 32A-32B illustrate the angle between the central longitudinal axis 902, which is parallel to pushwire 2708, and a line 3204, or 3206 respectively, from the proximal junction to the distal end of a primary strut of a flow modulation member in, respectively, working state and resting state. The change in the angle results a residual outward radial force on the blood vessel walls 114. As illustrated in FIG. 32A, during working state, when the umbrella of the flow modulation member is constrained by blood vessel walls 114 at distal radius 3210, this angle is referred to as the working angle 3200. As illustrated in FIG. 32B, during resting state, when the umbrella of the flow modulation member is deployed but not constrained by blood vessel walls 114 at distal radius 3212, this angle is referred to as the set angle 3202. In most embodiments, the set angle is greater than the working angle. For example, the set angle 3202 in FIG. 32B may be 60 degrees, while the working angle 3200 in FIG. 32A may be 45 degrees. The appropriate umbrella length for a given blood vessel radius may be calculated from the set and working angles. Thus, the working angle 3200 and set angle 3202 may be used to determine the appropriate longitudinal extension in the working state 3208 and resting state 3214 of the umbrella along the central axis 902.

The extent of the latitudinal expansion of a flow modulation member for a given translation of a microcatheter is another consideration when determining the slope(s) and/or length(s) of the primary struts. In certain embodiments, a rapid expansion of an umbrella-like flow modulation member with minimal translation of the microcatheter may be desirable. In other embodiments, a more gradual expansion may afford greater control. The optimal rate of flow modulation member deployment, such as umbrella expansion, per pushwire translation may be varied depending on the procedure and status of the clot.

According to some embodiments, the resistance of a flow modulation member against blood flow and its outward radial force against the blood vessel wall varies at different points of its profile.

In some embodiments, a flow modulation member is designed so that the radial force changes over the course of the member's deployment, to minimize friction between the member and the blood vessel wall. For example, in certain embodiments, the radial force of an umbrella-like flow modulation member may decrease as the radius of the partially deployed umbrella approaches that of the blood vessel. In alternative embodiments, a fully expanded flow modulation member may not completely contact the blood vessel wall. According to some embodiments, an operator may choose not to deploy the flow modulation member to its full extent. In cases where a flow modulation member does not contact or loosely contacts the blood vessel wall, only partial occlusion may be achieved and some blood may flow around the member.

In accordance with certain embodiments, the cross-sections of the self-expanding struts may take various shapes and dimensions in order to reach the targeted blood vessel wall with sufficient spring force to block blood flow. FIGS. 33A-33E illustrate five exemplary embodiments of primary strut cross-sections, including the depth 3300 and the width 3302. The depth 3300 of a strut is substantially parallel to a radial line 3304 from the central longitudinal axis 902 (along which the pushwire 2708 travels) to the blood vessel wall 114.

In the preferred embodiment of FIG. 33A, a rectangular cross-section of a strut is shown with a greater width 3302 (about 70 μm) than depth 3300 (about 50 μm), in order to increase the strut's ability to support an occlusion membrane. However, a greater depth 3300 may increase the ability of the struts to exert radial force. Therefore, a greater depth may be desired, as shown in FIG. 33B, where a rectangular cross-section of a strut is shown with a greater depth 3300 (about 70 μm) than width 3302 (about 50 μm). The square cross-section of a strut shown in FIG. 24C, with depth 3300 (about 70 μm) and width 3302 (about 70 μm), may be selected for both support and greater radial force. Generally, a square or rectangular cross-sectional shape may be easier to manufacture if cutting a strut from sheets, cones, or cylinders. Additionally, a square or rectangular cross-sectional shape may eliminate the need for electro-polishing to smooth the edges of a strut.

Other strut cross-sectional shapes are contemplated. For example, FIG. 33D illustrates a strut with an oval cross-section, having a greatest depth 3300 (about 50 μm) and greatest width 3302 (about 70 μm). Meanwhile, FIG. 33E illustrates a strut with a circular cross-section, having constant diameter (about 70 μm). In some embodiments of an umbrella-like flow modulation member, the shape and dimensions of a strut cross-section may even change across the length of the strut to achieve varying pressures and other characteristics at different points of the umbrella.

In accordance with preferred embodiments, the struts are made from nitinol. However, other shape-memory materials, shape-memory alloys, or super-elastic materials that exert pressure to expand to their set shape may be used. Such materials include, for example, nickel titanium alloy, stainless steel, or cobalt chromium alloys.

Different manufacturing methods may be used for the different types of struts. Struts may be formed out of a single piece of material or made from different pieces and assembled together. A single piece of material is preferred, when readily manufacturable, because it simplifies the attachment process and may afford greater structural integrity. Laser cutting may be used to manufacture the struts. For example, the struts may be cut from a cone that has an envelope similar to the desired expanded shape of an umbrella-like flow modulation member and a thickness as close as possible to the depth desired for the strut cross sections. Alternatively, the struts may be cut from a flat sheet of material or from a sheet of material that has been bent to the desired curvature of the struts. A substantially flat sheet of material will generally result in struts with rectangular cross sections.

Electro-polishing may or may not be needed, but may be used, in combination with the other methods described, to round the edges of individual struts to achieve oval or circular cross sections like those shown in FIGS. 33D and 33E respectively. In other embodiments, struts with oval or circular cross sections may be achieved by using thin wires. Likewise, bending and heat setting may or may not be used, in combination with the other methods described, to form and perfect the curvature of the struts.

In some embodiments, the primary struts of an umbrella-like flow modulation member may be cut from a single piece of material. The embodiment shown in FIG. 34A illustrates how this continuous piece has a ring-base 3402 at its proximal end. This ring-base 3402 is placed over and attached to the pushwire 2708. According to some embodiments, a ring-base 3402 is attached to the pushwire via thermal interference fitting. To use thermal interference fitting, the ring-base is made initially with a diameter too small to fit over the pushwire. When heated, the ring-base expands so it can be placed over the pushwire. As it cools, the ring-base tightens around the pushwire to create a firm attachment. Alternatively, the pushwire may be cooled to a low temperature such that the pushwire's diameter decreases. In this case, the ring-base would be manufactured at its final diameter. The ring-base is placed onto the cooled pushwire. As the pushwire expands to its normal diameter (at room temperature), it creates a firm attachment with the ring-base.

If the primary struts are made from separate parts, as shown in FIG. 34B-34D, the proximal ends of the struts 3404 must be securely attached to the pushwire 2708. The struts 3404 may be attached in any number of ways including but not limited to: welding the struts directly to the pushwire, soldering the struts directly to the pushwire (using, for example, platinum solder), or attaching the struts to a metal or plastic ring, which is either first or subsequently attached to the pushwire. The embodiment shown in FIG. 34C illustrates how the struts 3404 are attached to the pushwire 2708 with solder 3406.

In further embodiments, a sleeve or a low-profile ring may be placed on top of the various attachment junctions to promote smooth deployment and retrieval and to relieve strain on the attachments. FIG. 34D illustrates how a sleeve 3408 may be attached to the pushwire 2708 with solder 3406 to cover the proximal ends of struts 3404. A sleeve may be made of a heat-shrinkable material such as polyethylene terephthalate, nylon, or another polymer or elastic material. Adhesive, molding, press-fitting, interference fitting, curing, epoxy, or other attachment methods or combinations thereof may also be used to attach a sleeve.

As illustrated in FIGS. 35 and 36, according to some embodiments, a flow modulation member may incorporate secondary struts. The objectives of using secondary struts 3504 may include increasing pressure against blood flow at desired areas of the member, supporting a membrane of the member, and providing a closer fit between the member and blood vessel walls. For example, additional struts 3502 spaced between the secondary struts 3504 and around the distal end of an umbrella-like flow modulation member and/or additional struts 3504 around the mid-section of the member may be effective. The outer circle 3502 of the embodiment in FIGS. 35, 36 may represent the distal edge of a membrane, a secondary latitudinal strut, or both.

Distal secondary struts may advantageously facilitate contact between the distal open end of an umbrella-like flow modulation member and the luminal blood vessel wall by creating a more perfectly circular shape, instead of straight edges 3700 (as shown in FIG. 37) of membrane between the primary struts, thus better conforming the distal end of the member to the latitudinal plane of the vessel wall. This is illustrated, for example, in FIGS. 37 and 38 by the distal rounded distal edge 3702, instead of straight membrane edges 3700. In addition to more firmly engaging the blood vessel wall, secondary struts may minimize trauma to the blood vessel walls by improving the distribution of radial force. A variety of structures and techniques for improving and minimizing trauma are discussed above and below

Latitudinal struts may be added to the mid-section of an umbrella-like flow modulation member in order to further stabilize the member, make the mid-section of the umbrella more rigid, and/or exert pressure at various points against blood flow. The embodiments in FIGS. 35 and 36 also feature latitudinal struts 3604 (and potentially 3602) around the mid-section of the member.

The latitudinal struts need not be circular in configurations. In some preferred embodiments, a latitudinal strut is configured to include a series of straight sections and bends, which may be referred to as a zigzag configuration. For example, the embodiments in FIGS. 36, 38A and 38B feature a zigzag configuration for a latitudinal strut 3802(a). 3802(b) and 3604 at the distal end of an umbrella-like flow modulation member. In addition to a zigzag-configured latitudinal strut 3802 at the distal end of an umbrella-like flow modulation member, the embodiment in FIG. 36 features a zigzag-configured latitudinal strut 3602 around the mid-section of the member. The zigzag configuration is useful because it exerts latitudinal force while, as shown in FIG. 38B, folding up easily to contract back into the microcatheter 2706. Configurations other than zigzag may also be used for latitudinal struts. Of course, undulations and other wire patters are also desirable in certain design configurations.

In some embodiments, secondary struts include additional longitudinal struts that are not attached to the membrane of an umbrella-like flow modulation member. These stabilizing longitudinal struts may contact the blood vessel wall during deployment in order to center and further support the member. In certain embodiments, secondary struts include longitudinal struts that may pass through the hollow center of an umbrella-like flow modulation member, perhaps crossing the central axis 902.

According to some embodiments, secondary struts may be formed using the same materials with the same processes as primary struts. However, a secondary strut may have differently-shaped cross-section (e.g., a near-round cross-section) with a smaller diameter (e.g., about 50 μm) than the primary struts. Secondary struts may be attached to primary struts via methods including welding, soldering, or adhesion. However, in preferred embodiments, when efficient, the primary and secondary struts are cut from the same piece of original material.

In some embodiments, radiopaque materials may be attached to or used to make or coat a portion or all of the struts (or strut attachments, e.g., solder) of a flow modulation member. The radiopaque material or materials may include: platinum, cobalt, molybdenum, silver, tungsten, iridium, polymers, or various combinations. In preferred embodiments, three of the longitudinal struts are made from or coated with a radiopaque material. The marked struts may be equidistant from each other so that that state of expansion can be accurately observed from many angles. In a further preferred embodiment, a flow modulation member has platinum radiopaque markers welded to the distal ends of the primary struts. Alternatively, or in addition to marking the distal ends of the struts of a flow modulation member, radiopaque material may be used to mark the proximal ends of the struts, the pushwire at a point close to the base of the struts, the pushwire at points adjacent to where the open end of the flow modulation member touches when re-sheathed, and the distal end of the microcatheter.

Membranes

In accordance with some embodiments, the struts of an umbrella-like flow modulation member support a membrane, which blocks or slows the flow of blood when deployed in a vessel. In some embodiments, the membrane is flexible enough to allow the flow modulation member to pass through the brain's narrow and tortuous blood vessels. In preferred embodiments, the membrane is impermeable to blood and is elastic. To achieve these characteristics, the membrane of the umbrella may be constructed from various materials. Polypropylene is preferred but other materials may be used such as, thermoplastic polymers, elastomeric silicones, latexes, other polymers or a blend thereof. An example is ENGAGE™ polyolefin elastomers available from the Dow Chemical Company (Midland, Mich.). Elasticity allows the membrane to expand and contract with the movement of the struts. However, in other embodiments, the membrane need not be elastic, instead simply bending or folding with the movement of the struts. In some embodiments, the membrane need not even be impermeable.

In additional to polymers, the membrane may be made from other materials that block or slow blood flow, including types of woven fabric mesh or a web of fabric (e.g., made from Dacron). The membrane, as well as other or all parts of a flow modulation member, may be coated with a non-stick substance to reduce friction and enable easy movement through and upon exit from the microcatheter. Suitable friction-reducing or lubricating substances may include, but are not limited to, silicone-based lubricating agents, and polytetrafluoroethylene or other polymer coatings.

According to some embodiments, various parts of the flow modulation system may carry chemicals, pharmaceuticals, or other agents. For example, an umbrella-shaped flow modulation member or a reperfusion member may be coated with an agent. In a preferred method, an agent is held within the hollow space inside the umbrella, between the pushwire and the membrane.

According to preferred embodiments, the membrane material near the distal outer edge of an umbrella-like flow modulation member presents a rounded or even edge to the blood vessel wall. In order to conform to the blood vessel wall, the distal edge of the membrane may also be stiffer, thicker, and/or of a different material than the rest of the membrane. In the embodiment shown in FIG. 37, the distal edge 3702 of the membrane (identified at 3502 in FIG. 36) is both stiffer and thicker than the rest of the membrane 2702 but still of the same material. This alteration to the distal edge, which might otherwise consist of straight edges stretched between primary struts, conforms the distal edge of the membrane to the latitudinal plane of the blood vessel wall and thus creates a tighter seal. This is illustrated, for example, in FIG. 37 by the curved shape of the distal membrane edge 3702, instead of the straight membrane edges 3700. This form-asserting distal edge may also reduce friction between the flow modulation member and the blood vessel wall, limiting trauma to the blood vessel wall—that is already weakened from the ischemia. In preferred embodiments, and as shown in FIG. 39, the distal edge 3502 of the membrane 3900 extends past the distal ends of the struts 2908. In some embodiments, and as shown in FIG. 40, areas of the membrane proximal to the distal edge may be less rounded and instead stretched into straight membrane planes 4002.

In most embodiments, a method is used to connect the membrane to the primary struts that minimizes the possibility of the membrane detaching from the struts during deployment of the flow modulation member. Appropriate methods for attaching the membrane include, but are not limited to adhesion, or encasement of the struts either completely or partially.

In preferred embodiments, as shown in FIGS. 39, 40, 42A-42D and 43 an umbrella-like flow modulation member has a membrane 3900 that completely encases the struts in the latitudinally expanding regions of the member. Encasement may be accomplished, for example, by melting and molding the plastic around the struts. This is illustrated by section view 42C-42C in FIG. 42A, FIG. 42C, as well as FIG. 43, where the struts 2704 are illustrated as embedded within the membrane 3900. As illustrated in FIG. 29, if the struts 2908 and ring-base 2902 are one piece, and if a membrane encases the struts 2908, then the proximal membrane edge may be near the distal edge of the ring-base 2904. The view in FIG. 41E illustrates the ridges created by the struts in the membrane 3900.

In another attachment solution FIG. 39, an attachment ring 3902 may be a separate piece and made of a material such as steel or other metallic or non-metallic material. The attachment ring 3902 is compressed, using swaging, over the proximal ends of the flow modulation member and the pushwire 2708. Swaging creates even sealing without heating the nitinol, which would potentially alter the flow modulation member's shape memory.

In alternative embodiments, a membrane may be attached to the outside or inside of the struts of an umbrella-like flow modulation member. The embodiment shown in FIG. 44 shows a membrane 2702 attached to the outside of the primary struts 2704. This attachment of a membrane to the outside of the struts may be more efficient from a manufacturing perspective; however, attaching a membrane to the inside of the struts may reduce friction between the membrane and the microcatheter.

In some embodiments, the membrane is tapered to be, for example, thinner at its proximal end. In accordance with the embodiments shown in FIGS. 39 and 44, the membrane 2702 may extend toward the proximal end of the struts 2704 and into the attachment ring 3902. The membrane may extend into a ring or a sleeve covering the proximal base of the struts to create a good seal.

According to some embodiments illustrated in FIGS. 45A-45C, the shape or configuration that the flow modulation member's struts make when expanded may be different than an umbrella in appearance. The flow modulation member may take any shape or configuration capable of being deployed and retracted as well as capable of allowing the membrane to modulate blood flow. For example, a flow modulation member where the struts 4500 terminate together at the distal end may be used. FIG. 45A illustrates an embodiment of a flow modulation member with this shape attached to a pushwire 2708. Such embodiments pre-establish the placement and centering of the flow modulation system and allow an operator to verify that no sharp edges are making contact with the blood vessel wall. In addition, such embodiments have the advantage of increasing the contact area of the member with the blood vessel wall for greater stability, more easily ensuring a smooth curved contact area of the member with the blood vessel wall, and potentially fortifying the ability of the member to block blood flow. A membrane may cover the entire flow modulation member or a portion—any or a combination of the proximal portion, the distal portion, and the generally cylindrical portion in between—of the flow modulation member struts. In the embodiment shown in FIG. 45B, the membrane 4502 covers the proximal portion 4504 of flow modulation member. In the embodiment shown in FIG. 45C, the membrane 4508 covers the entire flow modulation member as represented by reference numeral 4506.

According to some embodiments, the flow modulation member may be designed so that the distal portion is not covered by a membrane and this uncovered distal portion is deployed before the membrane-covered portion. By deploying the uncovered portion first, an operator may secure the placement and trajectory of the flow modulation member prior to the active occlusion of blood flow. This allows the operator to deploy the membrane-covered portion more rapidly, safely, and confidently. To achieve these different effects across the membrane-covered and uncovered portions of a flow modulation member, the central cylinder portion may use a more pliable pattern than lattice, cellular, or other more rigid patterns. Straight struts, for example, would more easily allow part of the flow modulation member to be released while part remained in the microcatheter. The uncovered portions of the flow modulation member may remain expanded throughout postconditioning. In accordance with certain embodiments, a flow modulation member, particularly the primary struts, may be marked with radiopaque material to distinguish the membrane-covered and uncovered portions of the flow modulation member.

According to other embodiments, a flow modulation member may take the general form of a neurovascular stent. Neurovascular stents have a naturally cylindrical shape that is tangent to the blood vessel wall. A flow blocking membrane could be attached to cover all or part of a stent.

In further embodiments, the flow modulation member is part of the same element as the reperfusion member. FIGS. 46A-46C shows a series of hybrid clot capture and flow modulation member embodiments. In the embodiment shown in FIG. 46B, a flow-blocking membrane 4602 covers the proximal portion 4604 of a reperfusion member. A hybrid clot capture and flow modulation member may be less expensive and may be easier to retract back into the microcatheter and out of the body than multiple separate members. Besides reducing the number of moving parts, a hybrid clot capture and flow modulation member may allow flow modulation closer to the clot.

In order to accommodate the membrane, a hybrid clot capture and flow modulation member may need to be longer than a typical reperfusion member. FIG. 46C illustrates the distal clot contact area 4606 with this increase in length 4608, which may be, for example, 10 mm. According to most embodiments, the proximal end of a hybrid clot capture and flow modulation member would need to be positioned close enough to the microcatheter so that a minimal push of the microcatheter could re-sheathe the flow-blocking membrane during postconditioning. Additional modifications may be made to allow a hybrid clot capture and flow modulation member to remain partially deployed without significantly deforming the portion of the member in contact with the clot. For example, as illustrated in FIGS. 47A and 47B, an area of the cylindrical portion 4608 (show schematically as reference numeral 4612) between the membrane 4604 and the contact area 4606 for the distal clot 4710 may be made more structurally flexible or proximally tapered to dissipate the deforming force of re-sheathing on the distal clot contact area 4606. FIGS. 47A and 47B illustrate the clot contact area schematically.

Methods of Using Catheter-Constrained Embodiments of a Flow Modulation Member

FIGS. 48A and 48B are process flow charts for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIG. 48 may be applied to assemblies with catheter-constrained embodiments of a flow modulation member.

In step 4801, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 4802, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In optional step 4803, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the large catheter to a position distal to the location of the clot.

In step 4804, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. In step 4805, the guidewire is removed from the microcatheter and replaced with a pushwire. The pushwire has a flow modulation member and a reperfusion member coupled to the pushwire near the pushwire's distal end. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 4806, the active region will expand and engage with the clot. Depending on the distance that the microcatheter is translated proximally, the flow modulation member may either be deployed or sheathed while the reperfusion member's active region continues to contact the clot. During all passes with a clot-capturing reperfusion member, the microcatheter should be sufficiently retracted, at some point, so that the reperfusion member contacts the clot.

Following step 4806, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter and performing angiography to view the diffusion of the contrast agent. The flow modulation member must be at least partially sheathed for some time to allow diffusion of the contrast agent. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If the artery is not reperfused, then proceed to step 4807 in order to wait and check reperfusion status again. If reperfusion has occurred then proceed with either (1) postconditioning 4810, if postconditioning has not been already performed on a prior pass; or (2) step 4811, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously. Postconditioning cycles, of occlusion and reperfusion, are performed by translating the microcatheter, while holding the pushwire in place, to release (unsheathe) and constrain (resheathed) the flow modulation member and thereby blocking and unblocking the artery to varying degrees, respectively. The inflation/deflation may be performed either manually (e.g. by translation of the microcatheter by the operator) or automatically (e.g. with the translation of the microcatheter and timing thereof made by a computerized control system). Beneficial agents may be delivered during postconditioning or other times through the intermediate catheter (if present), large catheter, and microcatheter; however, these agents will only be able to directly reach the infarct region at times when the flow modulation member is not fully expanded against the blood vessel wall.

In step 4806, if the blood vessel has not been sufficiently reperfused, then proceed to step 4807 where the microcatheter is alternatively translated proximally and distally while the reperfusion member is held in place, in order to unsheathe and re-sheathe the flow modulation member in cycles. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 4808 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 4809 with the insertion of a new guidewire. Steps 4804-4809 are repeated in subsequent passes until either (1) the blood vessel is sufficiently reperfused, in which case proceed with either step 4810 if postconditioning has not been already performed or step 4811 if postconditioning performed previously, or (2) the predetermined maximum number of passes has been completed, in which case proceed with step 4813.

If the blood vessel is sufficiently reperfused after step 4806 or step 4807, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member is reversibly deployed in step 4810 according to a determined series of one or more postconditioning cycles. Examples of postconditioning cycles are described in greater detail elsewhere herein.

By having a blood flow-occluding flow modulation member unsheathed, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, this increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 4811. In a given pass, after unsheathing the clot-capturing reperfusion member in step 4806 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the intermediate catheter (if present) and/or the larger catheter. Therefore, the intermediate and/or larger catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 4812, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 4812, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 4813. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 4809 with the insertion of a new guidewire.

Primarily Electrically Controlled Flow Modulation Member

The degree of occlusion effectuated by the flow modulation member may be directly controlled by electricity. One way to do this is with an electro-active polymer (“EAP”). An example embodiment using an EAP to control the postconditioning cycles of the flow modulation member uses a configuration similar to the umbrella flow modulation member described elsewhere herein, but replaces the nitinol struts of the umbrella with struts made from an EAP.

In an example embodiment illustrated in FIGS. 49A-49B, includes sheets of EAP which are cut in bands of ˜750 μm wide and ˜2 mm long to form EAP struts 4908. The bands can be a parallelepiped preferentially with rectangular faces although other shapes are acceptable. The EAP struts may be encased in a membrane 3900 (as illustrated). The struts are secured to the pushwire 2708. The proximal ends of the struts are not encased in the membrane. Instead, they are sandwiched between two electrode rings 4904 and 4906. The two electrodes 4904 and 4906, the struts 4908 and the proximal part of the membrane 4912 are all securely attached to the pushwire 2708 by a surrounding attachment ring 4902, fastened by a method such as crimping. Two opposite faces of the EAP struts are illustrated perpendicular to a plane containing the symmetry axis of the pushwire and the longest dimension. Each face is connected to a wire 4940 and 4942 able to conduct electricity running along the pushwire and can be connected to a voltage source such as a battery, outside of the patient through connectors.

The application of a voltage between the two faces of the electroactive polymer causes the strut to bend in one direction. Usually the cations contained in the polymer are able to migrate (although this is not always the case), they are thus attracted towards the face of the polymer that is negatively charged, causing the polymer to bend. In this embodiment, we choose to connect the voltage source such that the polymer will bend with its face with the lower curvature—or greater radius of curvature—closer to the pushwire 2708. In this configuration, three to eight struts are distributed radially around the pushwire with their longest dimension in the direction of the central axis 902, and all bending away from the central axis when an appropriate voltage is applied. The voltage necessary to induce the deformation of the electroactive polymer struts is in the range of approximately 0.1-20V although a greater potential difference may be needed.

The struts create a scaffold for a membrane attached to them. One way of attachment is encasing the struts within the membrane, as depicted in FIGS. 49A and 49B. This membrane can be made from a polymer such as latex, elastomers, PETE or fabric such as Dacron®. The role of the membrane and supportive scaffolding electroactive struts is to reduce the flow in the artery when the struts. This embodiment functions in a similar manner as the umbrella-like flow modulation assembly. As the voltage is applied, the struts of electroactive polymer bend and contact the artery wall, deploying the membrane in the lumen of the artery thus reducing the cross-sectional area of the lumen available for the blood to flow through. When the apparatus is not connected to any external voltage source, the struts contract radially to their former position, ending up flush against the pushwire. In this state, blood could flow with minimum resistance. In this embodiment, postconditioning is achieved by connecting intermittently the voltage source to the electroactive polymer assembly. As previously described, this step is performed following partial or complete reperfusion of the blocked artery using a reperfusion member. When the source is connected to the electroactive polymer flow modulation device, the electroactive polymer struts are bent and the membrane is deployed in the artery, and they reduce blood flow to a near occlusion. Conversely, when the electroactive polymer flow modulation device is disconnected the struts and membrane are in a configuration flush to the pushwire and flow is increased. By intermittently connecting the voltage source, blood flow can effectively be modulated.

In some embodiments, an operator uses radiopaque markers as reference points to monitor and gauge the position of members, the state of member expansion, and the appropriate distances to move the microcatheter or pushwire.

Methods of Using Primarily Electrically-Controlled Flow Modulation Members

FIG. 50 is a process flow chart for performing postconditioning with mechanical thrombectomy (an example of one of the various techniques for achieving reperfusion) in accordance with some embodiments of the present invention. For example, the steps in FIG. 50 may be applied to assemblies with a primarily electrically-controlled flow modulation member.

In step 5001, a large catheter (e.g., a 6 French catheter) is inserted and guided, for example, from the femoral artery to the neck. In step 5002, a guidewire is inserted through the large catheter and navigated so that its distal end is at a position distal to the location of the clot, for example, in a cerebral artery.

In optional step 5003, an intermediate catheter (e.g., a 5 French catheter) is inserted over the guidewire and advanced so that its distal end is at a position (e.g., the sphenoidal (M1) segment of the middle cerebral artery) that is closer to the clot than the distal end of the large catheter. In the event of subsequent passes, an intermediate catheter saves time in navigating a new guidewire from the distal end of the large catheter to a position distal to the location of the clot.

In step 5004, a microcatheter is inserted over the guidewire and advanced so that its distal end is at a position distal to the clot. In step 5005, the guidewire is removed from the microcatheter and replaced with a pushwire. Electricity may be used to control the degree of occlusion, caused by the flow modulation member, through various mechanisms including changing the voltage developed across an EAP. In some embodiments, increasing the voltage potential causes the EAP to bend outward and, spreading an occlusive membrane outward and increasing occlusion. The pushwire has a reperfusion member coupled near its distal end. An EAP flow modulation member may be coupled to the pushwire. Some reperfusion members (such as those that may have clot-capture functionality) may have a self-expanding region adapted for engaging with a clot (i.e., an “active region”). If using a clot-capturing reperfusion member, the active region of the reperfusion member may be advanced within the microcatheter so as to be adjacent to the clot. Thus, when the microcatheter is retracted proximally to unsheathe the reperfusion member, as in step 5006, the active region will expand and engage with the clot. During all passes with a clot-capturing reperfusion member, the microcatheter should be sufficiently retracted so that the reperfusion member contacts the clot. If an EAP flow modulation member is coupled to the pushwire, the microcatheter should not be covering the flow modulation member (at least at times when the flow modulation member is intended to be expanded to occlude the artery). A control handle (“voltage controller”), containing a voltage source such as a battery, is affixed to the proximal end of the pushwire. By affixing the voltage controller, the electrical connectors from the voltage source join the wires 4940 and 4942 that develop voltage across the EAP. A switch on the voltage controller is pressed, developing voltage across the EAP and causing the EAP to bend outward and spread an occluding membrane across the blood vessel. Conversely, reducing the voltage potential contracts the occluding membrane and unblocks the vessel.

Following step 5006, the status of reperfusion should be assessed and the elapsed time tracked. The reperfusion status may be assessed by, for example, injecting a contrast agent (e.g., a bolus of radiopaque solution) through the large catheter, microcatheter, or intermediate catheter if applicable, and performing angiography to view the diffusion of the contrast agent. The voltage potential through the EAP must be reduced in order to allow the contrast agent to diffuse through the vessel. Suitable contrast agents may include, but are not limited to, iothalamate meglumine, diatrizoate meglumine, and other iodine-containing solutions. If reperfusion has occurred then proceed with either (1) postconditioning 5010, if postconditioning has not been already performed on a prior pass; or (2) step 5011, which consists of extracting the microcatheter and pushwire from the body, if postconditioning was performed previously. To deliver beneficial agents during postconditioning through the catheters, the occlusion caused by the flow modulation member can be temporarily removed by changing the voltage potential across the EAP in order to contract the occluding membrane.

In step 5006, if the blood vessel has not been sufficiently reperfused, then proceed to step 5007 where voltage potential is developed across the EAP, thus causing occlusion of the blood vessel. A determined period of wait-time “t” (e.g., about 5 minutes) is allowed so that the clot-capturing reperfusion member may expand into and engage with the clot. After wait time t, the flow modulation member is deflated and the status of reperfusion is assessed again. If the blood vessel has not been adequately reperfused, proceed with step 5008 where the microcatheter and pushwire are removed. If a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 5009 with the insertion of a new guidewire. Steps 5004-5009 are repeated in subsequent passes until either (1) the blood vessel is sufficiently reperfused, in which case proceed with either step 5010 if postconditioning has not been already performed or step 5011 if postconditioning performed previously, or (2) the predetermined maximum number of passes has been completed, in which case proceed with step 5013.

If the blood vessel is sufficiently reperfused after step 5006 or step 5007, postconditioning will be performed using the flow modulation member unless postconditioning was performed on a previous pass. If reperfusion is sufficient and postconditioning has not been performed on a previous pass, the flow modulation member is expanded and contracted in step 5010 according to a determined series of one or more postconditioning cycles. Sufficient voltage is maintained during the parts of the cycles where the occlusion is desired. Beneficial agents administered through the available catheters will be able to reach the infarct region or clot only when the umbrella is not fully occluding the vessel (e.g. during the reperfusion periods of the postconditioning cycle). Examples of postconditioning cycles are described in greater elsewhere herein.

By having the flow modulation member expanded so as to occlude the vessel, a stable hemodynamic environment is created, which helps minimize the risk of distal embolization. In some embodiments, expanding the umbrella concurrently with the deployment of the reperfusion member increases the benefits of postconditioning by controlling when reperfusion first occurs, so that postconditioning may be performed from the onset of reperfusion.

Upon removal of voltage potential from the EAP, the occlusion decrease and the flow modulation member gradually resumes its flush configuration. The voltage potential can be removed by causing the electrodes to disconnect from the voltage source. Upon contraction of the flow modulation member, the occlusion is gradually removed and the blood flow gradually restored.

If reperfusion is sufficient but postconditioning has already been performed on a previous pass, the microcatheter and pushwire are removed from the body in step 5011. In a given pass, after unsheathing the clot-capturing reperfusion member in step 5006 the operator should allow the clot-capturing reperfusion member to expand into the clot until wait time t has elapsed. To simultaneously remove the microcatheter and pushwire, an operator may hold the proximal ends of the pushwire and microcatheter together and translate them proximally until they are completely withdrawn from the body in accordance with some embodiments. The clot-capturing reperfusion member is not resheathed in the microcatheter during its exit from the body, but instead passes, along with the microcatheter and pushwire, within and through the intermediate catheter (if present) and/or the larger catheter. Therefore, the intermediate and/or larger catheters remain in place while the microcatheter and pushwire are removed from the body. Optionally, suction may be applied through the larger catheter and/or intermediate catheter to limit the dispersion of secondary emboli.

In step 5012, an operator determines whether clot material has been sufficiently removed by the clot-capturing reperfusion member. The status of reperfusion may inform this inquiry. Thus, in some embodiments, the status of reperfusion is assessed by, for example, injecting a contrast agent through the large catheter and performing angiography to view the diffusion of the contrast agent. In some embodiments, the reperfusion member itself is inspected (e.g., visually) to determine whether the degree of retrieved clot material is sufficient. Sufficiency may depend on numerous factors including, but not limited to, changes in perfusion.

Following step 5012, if a sufficient amount of clot material has been retrieved, as evidenced in some embodiments by the status of reperfusion, the procedure is completed and any remaining catheters are removed from the body according to step 5013. However, if none or an insufficient amount of clot material has been retrieved, and if a predetermined maximum number of passes has not yet been completed, a new pass is initiated in step 5009 with the insertion of a new guidewire.

Reperfusion Members

Embodiments of the reperfusion member allow an operator to treat a clot or embolus, usually to effectuate reperfusion. Examples of such treatment include removal (of all, part, or multiple pieces of the clot or embolus), maceration, lysis, compression, pushing, pulling, moving, dissolving, or maintaining in situ. According to some embodiments, a reperfusion member may resemble or comprise expandable stent technology, a corkscrew, a jackhammer, a lasso, a loop, a parachute, a filter, a cheese slicer, a vacuum, an inflatable object, a fishing net, a bottle brush, and/or ultrasound technology. The choice of a reperfusion member may depend on the conditions of a specific occluded blood vessel.

In certain embodiments, a reperfusion member may have acting components that are partially or entirely non-mechanical in nature. A reperfusion member may contain for release or be coated by chemical, pharmaceutical or other particular agents, which may act to, for example, lubricate the member, dissolve a clot, loosen a clot, cause a clot to contract, or increase the bonding of a clot with the reperfusion member. Such agents may also act on tissue surrounding a clot to, for example, vacillate, heal, minimize reperfusion injury, or minimize infarct size.

According to a preferred embodiment, a reperfusion member is based on retrievable stent technology. Retrievable stent technology is especially effective at achieving desired patient outcomes because of its ability to successfully enmesh and drag out large portions of clots. Retrievable stents may also be self-expanding and self-conforming to the size and shape of the blood vessel lumen, thus increasing the simplicity and safety of a clot-capturing reperfusion member. Generally, the central body (i.e., the part most likely to contact the clot) of a clot-capturing reperfusion member may be cylindrical. The central body may be connected to a pushwire by a plurality of struts. Both the proximal end and/or distal end may be either open, closed, tapered, and/or connected to a pushwire while maintaining an expandable cell structure. In some embodiments, the central body wraps around itself.

FIG. 51A illustrates an embodiment of the clot-capturing reperfusion member with a central body 5100 and closed distal end, both attached to a pushwire 106. Alternatively, FIG. 51B illustrates an embodiment of the clot-capturing reperfusion member with a central body 5100 and an open distal end 5104. FIG. SIC illustrates an embodiment of the clot-capturing reperfusion member with a central body 5100 and a plurality of struts 5106. Finally, FIG. 52 illustrates an embodiment of the clot-capturing reperfusion member with a central body that is not connected but wraps around itself 5200. This can be useful for a reduced profile for delivery, expansion of the reperfusion member, among other clinical benefits.

The preferred dimensions of a clot-capturing reperfusion member may be varied depending on, among other factors, the radius of the blood vessel, the radius of the clot, and the consistency or resistance of the clot. For example, the length of a clot-capturing reperfusion member may range from about 1 cm to 5 cm. At full expansion, the radius of a clot-capturing reperfusion member may range from about 1 mm to 4 mm.

The latitudinal resistive force may vary according to, among other factors: the dimensions of the clot-capturing reperfusion member, the dimensions of the struts, and the density of the cells. In addition, the latitudinal resistive force may change as the clot-capturing reperfusion member expands. Different latitudinal resistive properties may be desirable depending on the condition of the patient and of the clot.

In some embodiments, a clot-capturing reperfusion member is manufactured in a manner similar to a neurovascular stent, that is, the pattern of struts is laser-cut from a tube of suitable material, such as nitinol, and then electro-polished. Generally, embodiments of the clot-capturing reperfusion member may be manufactured using methods and materials described above or known in the art. In preferred embodiments, the expandable cell structure is made from a single piece of nitinol; however, separate pieces and other shape-memory materials, shape-memory alloys, or other super-elastic materials that tend to exert pressure to expand to their set shape may be used (e.g., nickel titanium alloy, stainless steel, or cobalt chrome alloy).

An alternative way of making the clot-capturing reperfusion member is to use separate pieces and attached them using a method such as soldering. Wires, struts, and cell components may be first cut as separate parts and then attached.

The proximal ends of the clot-capturing reperfusion member are attached to the pushwire in a similar manner as the umbrella's struts. In one attachment solution, an attachment ring 110 (illustrated in FIG. 34) may be a separate piece and made of a material such as steel. The steel attachment ring is compressed, using swaging, over the ends of the clot-capturing reperfusion member is struts and the pushwire. Swaging creates even sealing without heating the nitinol, which would potentially alter the clot-capturing reperfusion member's shape memory.

Radiopaque materials may be used to determine relative position, measure expansion, and gauge degree of clot entrapment. Radiopaque materials may include platinum, cobalt, molybdenum, gold, silver, tungsten, iridium, polymers, and combinations of various materials. In a preferred embodiment, as shown in FIG. 53, radiopaque markers 5302 are attached to the proximal and distal ends of a reperfusion member, and select cell segments running longitudinally through the central body are covered with a radiopaque coating 5304.

Cell Structures

Denser clots may and often do require multiple passes. This means that several unsuccessful—and time consuming—attempts are made to redeploy the device against the clot. A clot-capturing reperfusion member exerting greater radial force could help the member to grip the clot. A hexagonal cell structure may provide the right amount radial force. The wider angles of a hexagon (in comparison to a diamond) allow the clot-capturing reperfusion member to push against and into the clot more strongly, while still affording enough flexibility to be sheathed within the microcatheter.

The central body of a clot-capturing reperfusion member may be composed of various cell structures. Different cell geometries and dimensions (e.g., length, diameter, and pressure) may influence the extent and facility with which a clot-capturing reperfusion member engages with a clot. For example, larger cells, especially cells with narrower clot-facing width, may cut through a clot more easily. Meanwhile, smaller cells, especially cells with greater non-clot facing depth, may exert more overall pressure on a clot, tending to compress the clot against the blood vessel wall. Therefore, different cell geometries and dimensions may be desired for different situations, sizes and locations of clots or emboli.

FIG. 54 illustrates a preferred embodiment of the clot-capturing reperfusion member with a central body 5402 having a cylindrical structure with a plurality of individual cells 5404. According to some embodiments, the cell pattern may include a hexagon 5510 (shown in FIG. 55A), a quadrilateral 5512 (shown in FIG. 55B), a circle 5514 (shown in FIG. 55C), and/or an oval 5516 (shown in FIG. 55D). Accordingly, as shown by a two-dimensional diagram in FIG. 56, a cell structure pattern may include diamond-shaped cells 5602. In some embodiments, the cell structure pattern may resemble off-cycle wave curves. Among the above, embodiments with a hexagonal cell structure, as shown in FIG. 54, may provide superior radial force. A two-dimensional diagram of the same hexagonal cell pattern is shown in FIG. 57. Although the number and dimensions of the cells may vary, the length of one side 5702 of a hexagonal cell 5704 in the illustrated embodiment is 1.8 mm. In other embodiments, the cells may be stretched so that the cells are longer across the central longitudinal axis than they are wide.

Connecting junctions and other thicker parts of cells in a clot-capturing reperfusion member may be used and enhanced to facilitate clot adhesion to the member. FIG. 58 illustrates a strut junction 5802 with a greater radius than other parts of the struts and thicker parts, which may be on the outside 5804, the inside 5806, or both 5808 sides of a cell.

Strut Cross-Sections

According to some embodiments, the cross-sectional shape and dimensions of the struts in a reperfusion member may vary, both in general and within the same member. For example, the cross-sections of the struts in a reperfusion member may be circular, oval, or rectangular. In a preferred and particularly innovative embodiment, a reperfusion member uses an arrowhead-shaped strut cross-section to provide significant advantages for clot and embolus retrieval.

The strut cross-sections in a reperfusion member may affect the quality of its engagement with a clot. If a clot does not sufficiently adhere to a reperfusion member, multiple passes of the member may be required, thus complicating and prolonging the procedure. Even multiple passes do not guarantee successful engagement with a clot and may increase the risks, such as brain damage, associated with stroke. Furthermore, if a clot sufficiently adheres to a reperfusion member then emboli may be less likely to break away, migrate downstream, and irretrievably block smaller blood vessels.

In preferred embodiments, the reperfusion member has arrowhead-shaped strut cross-sections. Similar to how an arrowhead used for hunting pierces its target easily but is then difficult to dislodge, an arrowhead-shaped, or generally triangular, profile facilitates trapping a clot within the reperfusion member by piercing the clot yet providing more resistance to grip the clot after penetration and during retrieval. In most embodiments, the smallest angle (i.e., sharpest point) of the triangular cross-section points laterally outward toward the blood vessel wall (and clot) to facilitate clot penetration.

Numerous variations of an arrowhead-shaped or triangular cross-section may be used, with a few of these modifications exhibited in the embodiments of FIGS. 59A-59K. First, FIG. 59A illustrates an isosceles-triangle embodiment where the lengths of two sides 5900 and the other side 5902 of a triangular cross-section are, for example, 70 μm and 50 μm respectively. The attacking tip of the strut i.e., the edge that touches first the clot is depicted by reference numeral 5904. FIG. 59B illustrates an arrowhead-shaped embodiment with the same cross-section as the isosceles triangle except for a bend 5906 in the shorter side to increase the width of the inner side of the reperfusion member's struts. By providing more contact area on the inside of a reperfusion member, clot adhesion and compression may be improved. The same is true for other embodiments with cross-sections having wider base sides, such as the equilateral-triangle embodiment shown in FIG. 59C, the compressed isosceles-triangle embodiment shown in FIG. 59D, the isosceles-trapezoid embodiment shown in FIG. 59E (which may have a flattened surface 5910), the concave equilateral-triangle embodiment shown in FIG. 59I, the concave isosceles-trapezoid embodiment shown in FIG. 59J, and the concave half-oval embodiment shown in FIG. 59K. In particular, those embodiments with cross-sections having a bended or concave surface facing the reperfusion member's central longitudinal axis may further prevent a clot from migrating away from the member.

Next, FIG. 59F illustrates an isosceles-triangle embodiment where the smallest angle (i.e., point of greatest curvature sharpest point) 5908, which points laterally outward toward the blood vessel wall, has been dulled. By rounding the sharp edges of a reperfusion member in a process such as electro-polishing, trauma to the blood vessel walls is minimized. The same is true for other embodiments with cross-sections having dulled points 5908, such as the half-circle embodiment shown in FIG. 59G, the half-oval embodiment shown in FIG. 59H, and the concave half-oval embodiment shown in FIG. 59K.

FIG. 60A illustrates a hexagonal cell for an embodiment of the reperfusion member with the isosceles-triangle cross-section shown in FIG. 59A. In addition, FIG. 60B shows a three-dimensional section of strut with the same isosceles-triangle cross-section. The above modifications to the cross-sections may be used alone or in combination in a reperfusion member and/or a single strut of a reperfusion member.

Embodiments of the flow modulation system and its components may be used to perform reperfusion and/or postconditioning procedures. In one embodiment as shown in FIG. 61A, an operator may push a guidewire (not shown in the FIG. 61A), a microcatheter 6102 to a location proximal to a clot 6100 (also identified by reference numeral 4710 in earlier illustrations) in a blood vessel 6101. Then, in FIG. 61B, the operator may push the microcatheter 6102 past the clot 6100 so that the distal end of the microcatheter is distal to the clot. Often, the microcatheter 6102 follows the path of least resistance and maneuvers around the clot 6100 (as shown in FIG. 61C), wedging itself between the clot and the blood vessel wall 6101 (also reference numeral 114 in earlier illustrations), rather than passing directly through the clot. A pushwire 6106 with a flow modulation member 6112 and a reperfusion member 6110 may be positioned within the microcatheter 6102. In this embodiment the reperfusion member is a clot-capturing reperfusion member. However, various types of reperfusion members may be used. The operator may pull the microcatheter 6102 back (as shown in FIG. 61D) while the pushwire 6106 is held in place, unsheathing both the reperfusion member 6110 and the flow modulation member 6112, which self-expands to occlude blood flow. Meanwhile, the reperfusion member 6110 (also reference numeral 108 in earlier illustrations), which substantially spans the clot 6100 when unsheathed, may begin to self-expand (as shown in FIG. 61E), compressing the clot against the opposing wall of the blood vessel and reopening the occluded vessel for blood flow. Postconditioning may be performed at this point when recanalization first occurs.

The operator may push the microcatheter 6102 to partially re-sheathe (as shown in FIG. 61F) the flow modulation member 6112 and cause reperfusion. The operator may continue to pull (to deploy the flow modulation member 6112 and decrease flow) and push (to constrain the flow modulation member 6112 and increase flow) the microcatheter 6102, while holding the pushwire 6106 still, to cyclically modulate blood flow and achieve sufficient postconditioning before allowing natural reperfusion. The operator may facilitate these movements by using a handle or control member, as would be understood by those skilled in the art. The flow modulation member 6112 may be either opened or closed before reperfusion begins; however, in a preferred method, the flow modulation member is opened before reperfusion for more precise control over, and knowledge of when, reperfusion and postconditioning begins.

According to an embodiment using the flow modulation member shown in FIG. 27A-27C, described previously, an operator could push the associated microcatheter forward by about 3 mm to transition from having the modulation member fully deployed (blocking blood flow) to having the modulation member completely resheathed (allowing blood flow). In some embodiments, an operator may leave or hold the flow modulation member partially, or not fully, deployed to allow limited blood flow or to minimize friction with the blood vessel wall.

Examples of Postconditioning Cycles

The number and length of the time intervals for postconditioning may vary as determined by the operator. In FIG. 62A-62J, the y-axis represents the percentage of the cross-sectional luminal area of the blood vessel spanned by the flow modulation member normalized to its constrained state. Therefore, this graph does not take into account the effect of the clot or changes in unblocked space around the clot (i.e., if the flow modulation member is expanded so that it is stretches across 75% of the blood vessel, than the graph at that point in time is 75% shaded.) The x-axis is time in seconds. For example, the operator may choose more and/or longer cycle periods when the time from the onset of the ischemia is greater. An example of a desirable interval schedule may be about 6 alternating intervals of approximately 30 seconds unblocked 6200 and 30 seconds blocked 6202, as shown in FIG. 62B.

FIG. 62A is an example of an interval schedule with 3 alternating intervals of approximately 60 seconds unblocked and 60 seconds blocked. The transitions from unblocking to blocking as well as the transitions from blocking to unblocking occur rapidly as is indicated by the vertical slope on either side of the shaded (blocking) areas.

FIG. 62C is an example of an interval schedule with 1 alternating interval of approximately 600 seconds (ten minutes) unblocked and 600 seconds blocked. The transitions from unblocking to blocking as well as the transitions from blocking to unblocking occur rapidly as is indicated by the vertical slope on either side of the shaded (blocking) area.

FIG. 62D is an example of where the unblocked time is not equal to the blocked time, within the cycles. The different parts of the cycle can be of disparate time spans and may vary across cycles as well. The example depicted in FIG. 62D shows an interval schedule with 3 alternating intervals of approximately 30 seconds unblocked and 15 seconds blocked. The transitions from unblocking to blocking as well as the transitions from blocking to unblocking occur rapidly as is indicated by the vertical slope on either side of the shaded (blocking) areas.

FIG. 62E is an example of an interval schedule with 3 alternating intervals of approximately 15 seconds unblocked and 15 seconds blocked. The transitions from unblocking to blocking as well as the transitions from blocking to unblocking occur rapidly as is indicated by the vertical slope on either side of the shaded (blocking) areas.

FIG. 62A is an example of an interval schedule with 3 alternating intervals of approximately 60 seconds unblocked and 60 seconds blocked. The initial transition from blocking to unblocking is gradually (as indicated by the curved slope). Two possibilities explaining why this gradual reperfusion may occur are as follows: A first possibility is that the flow modulation member is not deployed as the reperfusion member gradually allows an increasing amount of flow through the vessel. A second possibility is that the flow modulation member is deployed as the reperfusion member expands. The flow modulation member gradually allows for an increase in flow at the beginning of postconditioning.

FIG. 62G is an example of an interval schedule where the flow modulation member steadily increases blocking at the beginning of the blocking portion of each cycle. The transitions from blocking to unblocking occur rapidly as is indicated by the vertical slope on the right-hand sides the shaded (blocking) areas.

FIG. 62H is an example of an interval schedule where the transitions from unblocking to blocking as well as the transitions from blocking to unblocking occur gradually as is indicated by the curved slope on either side of the shaded (blocking) areas. Additionally there is not a substantial period of unblocking between intervals.

FIG. 62I is an example of an interval schedule where the transitions from blocking to unblocking occur gradually as is indicated by the curved slope on the right-hand side of the shaded (blocking) areas. However, the transitions from unblocking to blocking occur rapidly. Gradual or partial occlusion with a flow modulation member may be used with the examples shown in FIGS. 62F-62J. In particular, FIG. 62J shows a postconditioning schedule where the degree of occlusion is non-linear. Meanwhile, the flow modulation member is deployed gradually for slower and steadier occlusion of a blood vessel, as can be seen from the progressive occlusion values in FIG. 62J. Postconditioning is preferred to be performed as close to the onset of reperfusion as possible. The actual degree of reperfusion achieved, as compared to normal flow rates, may vary depending on the degree to which reperfusion is achieved by the reperfusion member or the degree to which occlusion is achieved by the flow modulation member.

Each of the Embodiments of the flow modulation system or devices may also be used with chemicals, pharmaceuticals, or other agents to, for example: further minimize reperfusion injury, aid in removing a clot, or otherwise benefit a patient's condition. Agents that may minimize reperfusion injury include cyclosporine, sodium-calcium Na2+/Ca2+ exchange inhibitors, monoclonal antibodies, temperature reducing agents, or agents that slow cell metabolism. Agents that may aid in removing a clot include tPA and other agents that aid in dissolving, dislodging, or macerating clots. Agents that may otherwise benefit the patient's condition include pharmaceuticals commonly used for treating clots; agents for treating clots, preventing restenosis, or that commonly coat intravascular devices such as vasodilators; nimodipine; sirolimus; paclitaxel; anti-platelet compounds; agents that promote the entanglement or attachment of a clot with a reperfusion member; and anticoagulants such as heparin.

Any patents, publications, or other references mentioned in this application for patent are hereby expressly incorporated by reference.

As will be apparent to one of ordinary skill in the art from a reading of this disclosure, the present disclosure can be embodied in forms other than those specifically disclosed above. The particular embodiments described above are, therefore, to be considered as illustrative and not restrictive. Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. The scope of the present invention is as set forth in the appended claims and equivalents thereof, rather than being limited to the examples contained in the foregoing description. 

1. An assembly configured to treat ischemia in a patient, comprising: a catheter with a proximal region, a distal region, and a single lumen; a flow modulation member attached to the catheter and comprising an inflatable balloon configured to reversibly decrease and increase the flow of fluid through the blood vessel at least twice, and thereby modulate blood flow through the blood vessel, the flow modulation member comprises an inflatable balloon configured to receive a balloon inflation aperture continuous with the lumen; a pushwire with a proximal end and a distal end, wherein the pushwire is at least partially within the single lumen; a flow restoration member for increasing the flow of blood through the region of the clot, coupled to the distal end of the pushwire; and one or more sealing members attached to one of the pushwire and catheter adapted to decrease the flow rate of inflating fluid leaving the single lumen and inflate the balloon.
 2. The assembly of claim 1, wherein the one or more sealing members comprise a protrusion with an outwardly facing surface attached to the pushwire at a location on the pushwire proximal to the flow restoration member.
 3. The assembly of claim 2, wherein the protrusion further slows the flow of fluid through the lumen when the protrusion engages an inwardly facing surface toward the pushwire at the distal region of the catheter.
 4. The assembly of claim 1, wherein the catheter lumen comprises a first section in the proximal region and a second section in the distal region, the first section of the lumen having a first area in a plane normal to the catheter's central axis that is larger than a second area in the plane normal to the catheter's central axis in the second section of the lumen.
 5. The assembly of claim 1, wherein one of the one or more sealing members is electrically controlled, whereby an electric current applied to the pushwire causes the sealing member to expand so as to provide more resistance to the flow of fluid through the catheter, whereby the flow modulation member is capable of expanding to produce a desired seal in the blood vessel.
 6. The assembly of claim 1, wherein the assembly is adapted to operate with a pressure of the fluid less than 5 atm.
 7. The assembly of claim 1, wherein a pump configured to perform postconditioning cycles is connected to the lumen leading to the inflatable balloon to deliver inflating fluid.
 8. The assembly of claim 6, wherein the pump is configured to provide at least two cycles of inflation and deflation and wherein at least one of the cycles following the first cycle occurs without additional operator intervention.
 9. The assembly of claim 1, wherein the flow restoration member for increasing the flow of blood through a blood vessel beyond a clot comprises a self-expanding scaffold, adapted to engage a clot in a blood vessel.
 10. The assembly of claim 1, wherein the one or more sealing members comprise a sealing tip at the distal end of the catheter, wherein a luminal edge of the sealing tip comes in close proximity with a sealing surface of the pushwire and slows the flow of fluid through the lumen when the sealing surface of the pushwire is placed through the sealing tip.
 11. The assembly of claim 9, wherein the sealing tip allows the flow restoration member to pass the sealing tip when the catheter is translated relative to the pushwire.
 12. An apparatus comprising: a catheter; a balloon disposed on the catheter at a distal end of the catheter, the catheter defining a lumen and including an orifice for inflating the balloon; a clot capturing reperfusion member located near a distal end of the wire, the wire being partially within the lumen of the catheter; and a sealing interface between the wire and the lumen, nearer to the distal end of the catheter than is the orifice for inflating the balloon and adapted to seal the lumen so that the balloon may be inflated.
 13. The apparatus of claim 12, wherein the sealing interface includes an outwardly facing surface of the wire and surface of the lumen facing the pushwire.
 14. The apparatus of claim 13, wherein the inwardly facing sealing surface of the lumen has a smaller diameter than other portions of the lumen of the catheter.
 15. The apparatus of claim 13, wherein the outwardly facing surface of the wire has a larger diameter than other portions of the wire. 16-56. (canceled)
 57. An assembly able to treat ischemia in the neurovasculature of a patient, comprising: a catheter with a proximal end, a distal end, and at least two catheter lumina; one or more flow modulation members coupled to the catheter and comprising an inflatable balloon configured to reversibly decrease and increase a flow of fluid through a blood vessel at least twice, wherein the inflatable balloon has a balloon lumen continuous with a first catheter lumen and configured to receive inflating fluid from the first catheter lumen, wherein a distal end of the first catheter lumen is closed; one or more pushwires each with a proximal end and a distal end, wherein a first pushwire of the one or more pushwires is placed at least partially within a second catheter lumen; and one or more flow restoration members are coupled to the first pushwire near a distal end of the first pushwire.
 58. The assembly of claim 57, wherein a flow restoration member of the one or more flow restoration members comprises a self-expanding scaffold configured to engage a clot in a blood vessel.
 59. The method of claim 57, wherein a pump configured to perform postconditioning cycles is connected to the lumen leading to the inflatable balloon to deliver inflating fluid.
 60. The method of claim 59, wherein the pump is configured to provide at least two cycles of inflation and deflation and wherein at least one cycle after the first cycle occurs without additional operator intervention. 61-113. (canceled) 